CN111201229A

CN111201229A - Bicyclic compounds useful as RIP1 kinase inhibitors

Info

Publication number: CN111201229A
Application number: CN201880066460.0A
Authority: CN
Inventors: 陈慧芬; G·汉密尔顿; S·帕特尔; 赵桂玲; B·达涅尔斯; C·斯蒂瓦拉
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2017-10-11
Filing date: 2018-10-10
Publication date: 2020-05-26
Anticipated expiration: 2038-10-10
Also published as: IL273443A; MA50356A; CN111201229B; RU2020114670A; BR112020007067A2; CR20200151A; CA3078653A1; PH12020550253A1; EP3694858B1; CL2020000944A1; PE20211246A1; JP2020536915A; US11673892B2; US20200283446A1; AU2018348930A1; MX2020003439A; EP3694858A1; JP7362600B2; KR20200070297A; CO2020004977A2

Abstract

The present invention provides novel compounds having the general formula (I) or a pharmaceutically acceptable salt thereof (wherein R is^A、R^B1、R^B2Ring a and ring B are as described herein), pharmaceutical compositions comprising the compounds, and methods of using the compounds as RIP1 kinase inhibitors.

Description

Bicyclic compounds useful as RIP1 kinase inhibitors

Cross Reference to Related Applications

This application claims priority to U.S. provisional application No. 62/570,892 filed on 2017, 10, 11, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to organic compounds useful for therapy and/or prophylaxis in mammals, and in particular to RIP1 kinase inhibitors useful for the treatment of diseases and conditions associated with inflammation, cell death, and the like.

Background

Receptor interacting protein-1 ("RIP 1") kinase is a serine/threonine protein kinase RIP1 is a regulator of cell signal transduction that is particularly involved in the mediation of programmed cell death pathways such as necrotic apoptosis (necroptosis). the best studied form of necrotic (necroptotic) cell death is initiated by TNF α (tumor necrosis factor), but necrotic apoptosis can also be induced by other members of the TNF 84 death ligand family (Fas and TRAIL/Apo2L), interferons, Toll-like receptor (TLR) signaling, and viral infection by DNA sensor I (DNA dependent kinase of interferon regulatory factor) induces [1-3 ]. TNF α binding to TNFR 6336 (TNF receptor 1) causing trimerization of TNFR 1and formation of intracellular Complex-I. TRADD (TNF receptor related death domain) binding to the intracellular death domain of TNFR 1and by the intracellular death domain of the kinase found in two proteins [ RIP 638 ] kinase and phosphorylation domain of the necrosis receptor related death domain (TNF receptor related death domain) is completely blocked by the kinase (RIP kinase) phosphorylation of kinase 7 to the necrosis receptor kinase 7, which is initiated by the kinase, or the phosphorylation of the kinase receptor kinase 5 kinase, which is initiated by the phosphorylation of the kinase, which is initiated by the activation of the intracellular Complex of the kinase, or the phosphorylation of the necrosis factor kinase, which is initiated by the intracellular Complex of the kinase (RIP kinase) activation of the kinase 7-related death domain of the kinase 7 kinase, which is initiated by the intracellular Complex of the intracellular death domain of TNF 638 kinase (RIP kinase 7-related death domain, which is initiated by the intracellular Complex of TNF 638, which is initiated by the intracellular death domain of the intracellular death domain, which is initiated by the intracellular death domain of TNF 638, which is initiated by the kinase, which is initiated by the activation of the kinase, which is initiated by the kinase 7, or upon the activation of the phosphorylation domain of the kinase (RIP kinase 7, the phosphorylation domain of the kinase 7, the kinase, the phosphorylation of the kinase, the death domain of the kinase 7, the death domain of the kinase, the phosphorylation of the kinase, or.

Necrotic apoptosis has important pathophysiological relevance in myocardial infarction, central stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel disease, retinal degeneration and many other common clinical diseases [16 ]. Therefore, selective inhibitors of RIP1 kinase activity are expected as potential treatments for diseases mediated by this pathway and associated with inflammation and/or necrotic cell death.

Inhibitors of RIP1 kinase have been previously described. The first published inhibitor of RIP1 kinase activity was necrostatin 1(Nec-1) [17 ]. This initial discovery was followed by a modified version of Nec-1[11,18] with a different ability to block RIP1 kinase activity. More recently, additional RIP1 kinase inhibitors have been described that differ structurally from the neostatin class of compounds [19,20,21 ].

Each of the above-cited references is incorporated herein by reference in its entirety:

1) vanden Berghe, t., Linkermann, a., joean-Lanhouet, s., Walczak, h., and vandenabelle, P. (2014) Regulated necross: the expansion network of non-adaptive cell death routes Nature reviews molecular cell biology 15, 135-147.

2) Newton, K. (2015) RIPK 1and RIPK 3: criteria rules of information and cell depth. trends in cell biology.25, 347-.

3) de Almagro, m.c. and Vucic, d. (2015) neuroptosis: semin Cell Dev biol.39, 56-62.

4)Chen，Z.J.(2012)Ubiquitination in signaling to and activation ofIKK.Immunological reviews.246，95-106.

5) O' Donnell, M.A., Legarda-Addison, D., Skountzos, P., Yeh, W.C., and Ting, A.T, (2007) authentication of RIP1 rules NF-kappaB-independent cell-detathwitch in TNF signaling.Current biol.17, 418-424.

6) Feoktisova, M., Geserick, P., Kellert, B., Dimitrova, D.P., Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G., and Leverkus, M. (2011) cIAPs blockaptotome format, a RIP1/caspase-8 conditioning intercellated cell characterized complex differential modulated by cFLIP isof. molecular cell.43, 449-.

7) Bertrand, M.J., Milutinovic, S., Dickson, K.M., Ho, W.C., Boudreault, A., Durkin, J., Gillard, J.W., Jaquith, J.B., Morris, S.J., and Barker, P.A. (2008) cIAP 1and cIAP2 factitious cell subset functioning by E3 ligands and proton pump RIP 1. simulation. cell 30, 689. cell 700.

8) Wang, L., Du, F. and Wang, X. (2008) TNF-alpha indeces two stop caspase-8activation path. cell.133, 693-.

9) He, S. Wang, L. Miao, L. Wang, T. Du, F. Zhao, L. and Wang, X. (2009) receptational protein kinase-3 degrees cellular nuclear stress to TNF-alpha. cell.137, 1100-1111.

10) Cho, Y.S., Challa, S., Moquin, D., Genga, R., Ray, T.D., Guildford, M, and Chan, F.K. (2009) Phosphorylation-drive assembly of the RIP1-RIP3 complex modulated surgery. cell.137, 1112-1123.

11) Degterev, A., Hitomi, J., Germscheid, M., Ch' en, I.L., Korkina, O., Teng, X., Abbott, D., Cuny, G.D., Yuan, C., Wagner, G., Hedrick, S.M., Gerber, S.A., Lugovskoy, A. and Yuan, J. (2008) Identification of RIP1 kinase a specific cellular target of neural fibers Nat Chem biol.4, 313-321.

12) Newton, K.K., Dugger, D.L., Wickliffe, K.E., Kapoor, N.E., de Almagro, M.C., Vucic, D.E., Komuves, L.S., Ferrando, R.E., French, D.M., Webster, J.E., Roose-Girma, M.S., Warming, S.and Dixit, V.M. (2014) Activity of protein kinase RIPK3 determining amino cellulose by cloning or apoptosis Sci.343, 1357 and 1360.

13) Kaiser, W.J., Sridharan, H., Huang, C., Mandal, P., Upton, J.W., Gough, P.J., Sehon, C.A., Marquis, R.W., Bertin, J.and Mocarski, E.S, (2013) Toll-like receptor 3-processed neural RIP via TRIF, 3, and MLKL, the Journal of biological chemistry.288, 31268-.

14) Zhao, j., Jitkaew, s., Cai, z., Choksi, s., Li, q., Luo, j, and Liu, Z.G. (2012) Mixed linear enzyme domain-like a key receptor interaction protein3down stream component of TNF-induced diabetes.

15) Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., and Wang, X. (2012) Mixed Linear Motor Domain-like Protein medias Necrosis signalling Downstream of RIP3 Motor cell.148, 213-.

16) Linkermann, A. and Green, D.R. (2014) Necroptosis, the New England and jounalof medicine 370, 455-.

17) Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A., and Yuan, J. (2005) Chemical inhibitor of negative cell death with thermal potential for electrochemical bridge of blue titanium Biol.1, 112-119.

18) Takahashi, n., Duprez, l., Grootjans, s., Cauwels, a., nerrickx, w., DuHadaway, j.b., Goossens, v., Roelandt, r., Van Hauwermeiren, f., Libert, c., Declercq, w., Callewaert, n., prenergast, g.c., degerev, a., Yuan, j.and vandenabelle, p. (2012) neostatin-1 analogs: critical issues on the specification, activity and in vivo uses in experimental disease models cell Death dis.3, e437.

19) Harris, p.a., bandyophdayay, d., Berger, s.b., Campobasso, n, captiotti, c.a., Cox, j.a., Dare, l., Finger, j.n., Hoffman, s.j., Kahler, k.m., Lehr, r., Lich, j.d., Nagilla, r., Nolte, r.t., Ouellette, m.t., Pao, c.s., Schaeffer, m.c., Smallwood, a, Sun, h.h., Swift, b.a., toritis, r.d., Ward, marquard, p.w., Bertin, j.83 and go (1243) moisture, tre 20184, image, for example, moisture, RIP, image 3, for use of cellular telephone.

20) Najjar, m., Suebsuwong, c., Ray, s.s., Thapa, r.j., Maki, j.l., Nogusa, s., Shah, s., Saleh, d., Gough, p.j., Bertin, j., Yuan, j., Balachandran, s., Cuny, g.d., and degerev, a. (2015) structural designed of patent and selected passive components for ripk1.cell Rep.

21) International patent publication No. WO 2014/125444.

22) International patent publication No. WO 2017/004500.

Disclosure of Invention

Provided herein are compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R^ASelected from:

s is 0 or 1;

R¹selected from hydrogen, deuterium, fluorine, hydroxy, cyano, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy, via a (R)^N)₂C substituted by N substituents₁-C₆Alkyl radical, C₁-C₆Cyanoalkyl, C₁-C₆Alkylsulfonyl, phenyl, benzyl, 4-to 6-membered heterocyclyl and 5-to 6-membered heteroaryl;

wherein when R is¹Is phenyl, benzyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₃-C₆When cycloalkyl is present, said phenyl, C₁-C₆The alkoxy or cycloalkyl ring is optionally substituted with 1 to 2 substituents selected from: fluorine, chlorine, cyano, C₁-C₃Alkyl, cyclopropyl, C₁-C₃Alkoxy radical, C₁-C₃Hydroxyalkyl radical, C₁-C₃Haloalkyl, C₁-C₆Alkoxycarbonyl group, C₁-C₃alkoxy-C₁-C₃Alkyl and C₁-C₃A haloalkoxy group; r^2aAnd R^2bEach independently selected from hydrogen, deuterium, fluorine, hydroxyl, C₁-C₃Alkyl and C₁-C₃A fluoroalkyl group; provided that R is^2aAnd R^2bBoth cannot be hydroxyl; or

R¹Selected from hydrogen, deuterium, fluoro, methyl and cyano; and is

R^2aAnd R^2bTogether with the carbon atom to which they are both attached form a 4-to 6-membered heterocyclic ring or a 3-to 5-membered carbocyclic ring, each optionally substituted with 1 to 2 substituents selected from: fluorine, chlorine, hydroxy, cyano, C₁-C₃Alkyl, hydroxymethyl, methoxymethyl, C₁-C₄Alkoxycarbonyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

each R^NIndependently selected from C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy and C₁-C₆A haloalkyl group; or two R^NTogether with the nitrogen atom to which they are both attached form a 4-6 membered heterocyclic ring;

each R⁶Independently selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Cyanoalkyl, C₁-C₃Alkylcarbonyl group, C₁-C₃Methanesulfonyl group, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, formyl, C₁-C₆Haloalkoxy, cyano, 1-methyl-pyrazol-4-yl, and pyrimidinyl; and is

The ring A and the ring B are fused to form a polycyclic ring system, wherein

Ring a is a 5-membered heteroaromatic ring having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom or (iii) one nitrogen atom and one sulfur atom as its only heteroatoms; wherein ring a is optionally substituted at a carbon atom with one substituent selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl; and is

Ring B is a 4 to 8 membered carbocyclic ring, or a 4 to 8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

p is 1 or 2, and q is 0 or 1; or p is 0 and q is 1;

each R^B1Independently selected from halogen, deuterium, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Thioalkyl, C₁-C₆alkyl-N (R)^N)₂And a cyano group; two of which are C₁-C₆The alkyl substituents may together form a bridged or spiro ring; and wherein if the nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano or C having an oxygen or sulfur atom directly bonded to the nitrogen atom₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or C₁-C₆A thioalkyl group;

R^B2is selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Thioalkyl, C₁-C₆alkyl-N (R)^N)₂Phenyl, benzyl, CH₂-(C₃-C₆Cycloalkyl), CH₂CH₂-(C₃-C₆Cycloalkyl), CH₂- (4-to 6-membered heterocyclic group), CH₂CH₂- (4-to 6-membered heterocyclic group), 5-to 6-membered heteroaryl and CH₂- (5 to 6 membered heteroaryl); wherein when R is^B2In the case of phenyl or benzyl, the phenyl ring is optionally substituted with 1 to 3 substituents selected from: halogen, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy and cyano;

provided that when R is^AIs composed of

And R is^2aAnd R^2bEach being hydrogen, R¹Is not hydrogen, halogen or methyl; and is

With the further proviso that when ring B is substituted by C₁-C₆alkyl-N (R)^N)₂And phenyl substituted, and each

R^NIn the case of hydrogen, the acid is,

not methyl, tert-butyl, N-ethylmorpholino or methoxyethyl.

Also provided herein are pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Particular embodiments include pharmaceutical compositions suitable for oral delivery.

Also provided herein are oral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

Also provided herein are methods of treatment of diseases and disorders associated with inflammation, cell death, and other diseases and disorders associated with RIP1 kinase, as described further below.

Also provided herein are compounds or pharmaceutical compositions for use as therapeutically active substances.

Also provided herein is the use of the compounds or pharmaceutical compositions for the treatment of diseases and disorders associated with inflammation, cell death, and other diseases and disorders associated with RIP1 kinase, as further described below.

Also provided herein is the use of a compound or pharmaceutical composition in the manufacture of a medicament for the treatment of diseases and disorders associated with inflammation, cell death, and other diseases and disorders associated with RIP1 kinase, as further described below.

Also provided herein are compounds or pharmaceutical compositions for treating diseases and disorders associated with inflammation, cell death, and other diseases and disorders associated with RIP1 kinase, as described further below.

Detailed Description

Definition of

As understood by one of ordinary skill in the art, all chemical formulas and general chemical structures as provided herein should be interpreted to provide appropriate valencies and chemically stable bonds between atoms. Where appropriate, a substituent may be bonded to more than one adjacent atom (e.g., alkyl includes methylene in which there are two bonds).

In the formulae provided herein, "halogen" or "halo" refers to fluorine, chlorine and bromine (i.e., F, Cl, Br).

Unless otherwise specifically defined, alkyl refers to optionally substituted straight or branched chain C₁-C₁₂An alkyl group. In some embodiments, alkyl refers to C₁-C₆Alkyl radical. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Substituted alkyl groups provided herein are substituted with one or more substituents selected from: halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C₃-C₆Cycloalkyl, phenyl, OH, CO₂H、CO₂(C₁-C₄Alkyl), NH₂、NH(C₁-C₄Alkyl group), N (C)₁-C₄Alkyl radical)₂、NH(C＝O)C₁-C₄Alkyl, (C ═ O) NH (C)₁-C₄Alkyl), (C ═ O) N (C)₁-C₄Alkyl radical)₂、S(C₁-C₄Alkyl), SO (C)₁-C₄Alkyl), SO₂(C₁-C₄Alkyl), SO₂NH(C₁-C₄Alkyl), SO₂N(C₁-C₄Alkyl radical)₂And NHSO₂(C₁-C₄Alkyl groups). In some embodiments, substituted alkyl groups have 1 or 2 substituents. In some embodiments, an alkyl group is unsubstituted.

Unless otherwise specifically defined, cycloalkyl refers to optionally substituted C₃-C₁₂Cycloalkyl, and includes fused, spiro and bridged bicyclic radicals wherein the substituents are selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C₃-C₆Cycloalkyl, phenyl, OH, CO₂H、CO₂(C₁-C₄Alkyl), NH₂、NH(C₁-C₄Alkyl group), N (C)₁-C₄Alkyl radical)₂、NH(C＝O)C₁-C₄Alkyl, (C ═ O) NH (C)₁-C₄Alkyl), (C ═ O) N (C)₁-C₄Alkyl radical)₂、S(C₁-C₄Alkyl), SO (C)₁-C₄Alkyl), SO₂(C₁-C₄Alkyl), SO₂NH(C₁-C₄Alkyl), SO₂N(C₁-C₄Alkyl radical)₂And NHSO₂(C₁-C₄Alkyl groups). In some embodiments, cycloalkyl refers to C₃-C₆A cycloalkyl group. In some embodiments, C₃-C₆Cycloalkyl is optionally substituted with 1 to 3 halogen atoms. In some embodiments, C₃-C₆Cycloalkyl is optionally substituted with 1 to 3 fluorine atoms. Exemplary C₃-C₆Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary C₃-C₁₂Cycloalkyl also includes bicyclo [3.1.0]Hexyl, bicyclo [2.1.1]Hexyl, cycloheptyl, bicyclo [4.1.0]Heptyl, spiro [4.2 ]]Heptyl, cyclooctyl, spiro [4.3 ]]Octyl, spiro [5.2 ]]Octyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.2]Octyl, adamantyl, decahydronaphthyl and spiro [5.4 ]]A decyl group. The cycloalkyl group may be fused to other groups, where appropriate, such that there is more than one bond between the cycloalkyl group and another ring system (e.g., a C-ring of formula I). In some embodiments, a cycloalkyl group is unsubstituted.

Unless otherwise specifically defined, haloalkyl refers to straight or branched chain C₁-C₁₂Alkyl, wherein one or more hydrogen atoms are replaced by halogen. In some embodiments, haloalkyl refers to C₁-C₆A haloalkyl group. In some embodiments, 1 to 3 hydrogen atoms of the haloalkyl are replaced with a halogen. In some embodiments, each hydrogen atom of the haloalkyl is replaced with a halogen (e.g., trifluoromethyl). In some embodiments, haloalkyl is as defined herein, wherein in each instance halo is fluoro. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and pentafluoroethyl.

Unless otherwise specifically defined, alkoxy means straight or branched chain C₁-C₁₂Alkyl, in which one or more oxygen atoms are present in each case between two carbon atoms. In some embodiments, alkoxy refers to C₁-C₆An alkoxy group. In some embodiments, C provided herein₁-C₆The alkoxy group has one oxygen atom. Exemplary alkoxy packetsIncluding methoxy, ethoxy, CH₂OCH₃、CH₂CH₂OCH₃、CH₂OCH₂CH₃、CH₂CH₂OCH₂CH₃、CH₂OCH₂CH₂CH₃、CH₂CH₂CH₂OCH₃、CH₂OCH(CH₃)₂、CH₂OC(CH₃)₃、CH(CH₃)OCH₃、CH₂CH(CH₃)OCH₃、CH(CH₃)OCH₂CH₃、CH₂OCH₂OCH₃、CH₂CH₂OCH₂CH₂OCH₃And CH₂OCH₂OCH₂OCH₃。

Unless otherwise specifically defined, cycloalkoxy means C as defined above₄-C₁₀Or C₄-C₆Alkoxy, wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

Unless otherwise specifically defined, haloalkoxy means C as defined above₁-C₆Haloalkyl, wherein one or two oxygen atoms are present in each case between two carbon atoms. In some embodiments, C provided herein₁-C₆The haloalkoxy group has one oxygen atom. Exemplary haloalkoxy groups include OCF₃、OCHF₂And CH₂OCF₃。

Unless otherwise specifically defined, thioalkyl means a C as defined above in which the oxygen atom is replaced by a sulfur atom₁-C₆An alkoxy group. In some embodiments, thioalkyl groups may include sulfur atoms substituted with one or two oxygen atoms (i.e., alkyl sulfones and alkyl sulfoxides). Exemplary thioalkyl groups are those exemplified in the definition of alkoxy above, wherein each oxygen atom is replaced in each case by a sulfur atom.

Unless otherwise specifically defined, alkoxycarbonyl means wherein oxygen is presentC as defined above with atoms bonded to carbonyl groups to form esters₁-C₆An alkoxy group. Exemplary alkoxycarbonyl groups include CH₃OC (O) -and CH₃CH₂OC(O)-。

Unless otherwise defined, acyl, alkanoyl or alkylcarbonyl refers to a group of formula-C (═ O) R, where R is hydrogen or lower alkyl as defined herein. Formyl refers to a group of formula-C (═ O), where R ═ H. Arylcarbonyl or aroyl refers to a group of formula-C (═ O) R, where R is aryl; as used herein, the term "benzoyl" is "arylcarbonyl" or "aroyl" wherein R is phenyl.

Unless otherwise specifically defined, cyanoalkyl refers to C as defined above wherein one hydrogen atom is replaced by cyano ("-CN")₁-C₆An alkyl group. Exemplary cyanoalkyl groups include CNCH₂And CNCH₂CH₂-。

Unless otherwise specifically defined, alkylsulfonyl refers to a group in which a carbon atom is bonded to a sulfone group ("SO₂") the sulfone group is in turn bonded to C₁-C₆C of alkylene as defined above₁-C₆An alkyl group. Exemplary alkylsulfonyl groups include CH₃SO₂CH₂-and CH₃SO₂CH₂CH₂-。

Unless otherwise specifically defined, heterocyclyl refers to a single saturated or partially unsaturated 4-to 8-membered ring having at least one atom in the ring other than carbon, wherein the atom is selected from oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems (multiple condensed ring systems) having at least one such saturated or partially unsaturated ring, having from 7 to 12 atoms, and described further below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3,4, 5,6,7, or 8 membered ring) having from about 1 to 7 carbon atoms and from about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. The ring may be C-branched (i.e., by C)₁-C₄Alkyl substituted). The ring may be substituted by one or more (e.g. 1,2 or 3) oxo groups, and the sulphur and nitrogen atoms are alsoMay be present in its oxidized form. Exemplary heterocycles include, but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The rings of the multiple condensed ring system may be connected to one another by fused, spiro and bridged bonds, where valency is required. It is to be understood that the individual rings of the multiple condensation ring system may be linked in any order relative to each other. It will also be appreciated that the point of attachment of the multiple condensed ring system (as defined above for the heterocyclic ring) may be anywhere in the multiple condensed ring system. It will also be appreciated that the point of attachment of the heterocyclic ring or heterocyclic polycondensed ring system may be at any suitable atom of the heterocyclic group including carbon and nitrogen atoms. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3, 4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1, 2-dihydropyridinyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, 1, 4-benzodioxanyl, spiro [ cyclopropane-1, 1' -isoindolinyl]-3' -ketones, isoindolinyl-1-ones, 2-oxa-6-azaspiro [3.3]Heptyl, imidazolidin-2-one N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1, 4-dioxane, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro [3.3]Heptane, (1R,5S) -3-azabicyclo [3.2.1]Octane, (1s,4s) -2-azabicyclo [2.2.2]Octane, (1R,4R) -2-oxa-5-azabicyclo [2.2.2]Octane and pyrrolidin-2-one.

In some embodiments, heterocyclyl is C having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur₄-C₁₀A heterocyclic group. In some embodiments, heterocyclyl is neither bicyclic nor spirocyclic. In some embodiments, heterocyclyl is C having 1 to 3 heteroatoms₅-C₆Heterocyclyl, wherein at least 2 if 3 heteroatoms are present are nitrogen.

Unless otherwise specifically defined, aryl refers to a single all-carbon aromatic ring or a multiple condensed all-carbon ring system in which at least one ring is aromatic, and in which the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl. Aryl also includes multiple condensed ring systems having about 9 to 20 carbon atoms (e.g., ring systems containing 2,3, or 4 rings), wherein at least one ring is aromatic and wherein the other rings may be aromatic or non-aromatic (i.e., carbocyclic). Such a multiple condensed ring system is optionally substituted with one or more (e.g., 1,2 or 3) oxo groups on any carbocyclic moiety of the multiple condensed ring system. The rings of the multiple condensed ring system may be connected to one another by fused, spiro and bridged bonds, where valency is required. It is to be understood that the point of attachment of the multiple condensed ring system, as defined above, may be anywhere in the ring system, including the aromatic or carbocyclic moieties of the ring. Exemplary aryl groups include phenyl, indenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, anthracenyl, and the like.

Unless otherwise specifically defined, heteroaryl refers to a 5-to 6-membered aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen, and sulfur; "heteroaryl" also includes a multiple condensed ring system of 8 to 16 atoms with at least one such aromatic ring, which is described further below. Thus, "heteroaryl" includes a monoaromatic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "heteroaryl" also includes multiple condensed ring systems (e.g., ring systems comprising 2 or 3 rings), wherein heteroaryl is condensed with one or more rings selected from the group consisting of: heteroaryl (forming, for example, a naphthyridinyl group, e.g. 1, 8-naphthyridinyl group), heterocyclic (forming, for example, a 1,2,3, 4-tetrahydronaphthyridinyl group such as 1,2,3, 4-tetrahydro-1, 8-naphthyridinyl group), carbocyclic (forming, for example, a 5,6,7, 8-tetrahydroquinolinyl group), and aryl (forming, for example, an indazolyl group). Thus, heteroaryl groups (monoaromatic or polycondensed ring systems) have from 1 to 15 carbon atoms and about 1-6 heteroatoms in the heteroaryl ring. Such a multiple condensed ring system may be optionally substituted on the carbocyclic or heterocyclic moiety of the condensed ring with one or more (e.g. 1,2,3 or 4) oxo groups. The rings of the multiple condensed ring system may be connected to one another by fused, spiro and bridged bonds, where valency is required. It is to be understood that the individual rings of the multiple condensation ring system may be linked in any order relative to each other. It is also understood that the point of attachment of the multiple condensation ring system (as defined above for heteroaryl) may be anywhere in the multiple condensation ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic moiety of the multiple condensation ring system. It is also understood that the point of attachment of the heteroaryl or heteroaryl multiple-condensation ring system may be at any suitable atom of the heteroaryl or heteroaryl multiple-condensation ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7, 8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thioindenyl, pyrrolo [2,3-b ] pyridyl, quinazolinyl-4 (3H) -one, triazolyl, 4,5,6, 7-tetrahydro-1H-indazole, and 3b,4,4a, 5-tetrahydro-1H-cyclopropeno [3,4] cyclopenta [1,2-c ] pyrazole.

As used herein, the term "chiral" refers to a molecule having the property that the mirror partners (partner) are non-overlapping, while the term "achiral" refers to a molecule that can overlap on its mirror partners.

As used herein, the term "stereoisomer" refers to a compound having the same chemical composition, but differing in the arrangement of atoms or groups in space.

As used herein, a wavy line that intersects a bond in a chemical structure

Indicating phase with wavy lines in chemical structureThe point of attachment of the crossed bond to the rest of the molecule.

The term "C-linked" as used herein means that the group described by the term is attached to the rest of the molecule through a ring carbon atom.

The term "N-linked" as used herein means that the group described by the term is attached to the rest of the molecule through a ring nitrogen atom.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.

"enantiomer" refers to two stereoisomers of a compound that are mirror images of each other that are not superimposable.

The stereochemical definitions and conventions used herein generally follow the codes of S.P. Parker, McGraw-HillDirectionof Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention (including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures) are intended to form part of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to designate the sign of rotation of a compound for plane polarized light, with (-) or 1 indicating that the compound is left-handed. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. 50 of enantiomer: 50 mixtures are referred to as racemic mixtures or racemates, which can occur without stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, without optical activity.

When a bond in a formula of a compound herein is drawn in a non-stereochemical manner (e.g., flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a formula of a compound herein is drawn in a defined stereochemistry (e.g., bold-wedge, dashed or dashed-wedge), it is understood that the atom to which the stereochemical bond is attached is enriched for the absolute stereoisomer shown, unless otherwise indicated. In one embodiment, the compound may be at least 51% of the absolute stereoisomer described. In another embodiment, the compound may be at least 80% of the absolute stereoisomer described. In another embodiment, the compound may be at least 90% of the absolute stereoisomer described. In another embodiment, the compound may be at least 95% of the absolute stereoisomer described. In another embodiment, the compound may be at least 97% of the absolute stereoisomer described. In another embodiment, the compound may be at least 98% of the absolute stereoisomer described. In another embodiment, the compound may be at least 99% of the absolute stereoisomer described.

As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be converted to each other by a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions by proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversion by recombination of some of the bonded electrons.

As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

As used herein, the term "protecting group" refers to a substituent that is commonly used to block or protect a particular functional group on a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silane groups. "carboxy protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfinyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl, and the like. For a general description of protecting Groups and their use, see p.g.m.wuts and t.w.greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.

As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cattle, pigs, and sheep.

As used herein, the term "pharmaceutically acceptable salt" is meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat (neat) or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc salts and the like. Salts derived from pharmaceutically acceptable organic bases include salts of the following organic bases: primary, secondary and tertiary amines include substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge, s.m. et al, "Pharmaceutical salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the invention contain both basic and acidic functionalities such that the compounds can be converted to base or acid addition salts.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

In addition to salt forms, the present invention also provides compounds in prodrug form. As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical agent, it can be slowly converted to a compound of the invention.

Prodrugs of the invention include compounds wherein an amino acid residue or a polypeptide chain of two or more (e.g., 2,3, or 4) amino acid residues is covalently linked to a free amino, hydroxyl, or carboxylic acid group of a compound of the invention through an amide or ester bond, amino acid residues include, but are not limited to, the 20 naturally occurring amino acids typically represented by three letter symbols, and include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine (demosine), isobornysine (isodemosine), gamma-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, β -alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

Other types of prodrugs are also included. For example, the free carboxyl groups of the compounds of the present invention may be derivatized as amides or alkyl esters. As another example, compounds of the invention containing a free hydroxyl group may be derivatized into prodrugs by converting the hydroxyl group to a group such as, but not limited to, phosphate, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethoxymethoxycarbonyl, such as Fleisher, d. et al, (1996) Improved oral drug delivery: the solvent limiting solvent by the use of the drugs Advanced Drug Delivery Reviews, 19: 115. Also included are carbamate prodrugs of hydroxy and amino groups, as well as carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy) methyl and (acyloxy) ethyl ethers, where acyl groups may optionally be included but are not excludedAlkyl esters substituted with groups not limited to ether, amine and carboxylic acid functional groups, or where the acyl group is an amino acid ester as described above. Prodrugs of this type are described in j.med.chem., (1996), 39: 10. More specific examples include replacing a hydrogen atom of an alcohol group with a group such as (C)_1-6) Alkanoyloxymethyl, 1- ((C)_1-6) Alkanoyloxy) ethyl, 1-methyl-1- ((C)_1-6) Alkanoyloxy) ethyl group, (C)_1-6) Alkoxycarbonyloxymethyl, N- (C)_1-6) Alkoxycarbonylaminomethyl, succinyl, (C)_1-6) Alkanoyl, α -amino (C)_1-4) Alkanoyl, arylacyl and α -aminoacyl or α -aminoacyl- α -aminoacyl wherein each α -aminoacyl is independently selected from naturally occurring L-amino acids, p (o) (oh)₂、-P(O)(O(C_1-6) Alkyl radical)₂Or a glycosyl (the radical resulting from the removal of the hydroxyl group of the carbohydrate in the hemiacetal form).

For further examples of prodrug derivatives see, e.g., a) Design of produgs, eds. h.bundgaard, (Elsevier, 1985) and Methods in Enzymology, vol.42, p.309-396, eds. widder et al (academic press, 1985); b) a Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard, Chapter 5"Design and Application of produgs," by H.Bundgaardp.113-191 (1991); c) bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) d) H.Bundgaard et al, Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N.Kakeya et al, chem.pharm.Bull., 32:692(1984), each of which is expressly incorporated herein by reference.

In addition, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced by the metabolism of a particular compound or salt thereof in vivo. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

Metabolites are typically identified as follows: preparation of radiolabels of the Compounds of the invention (e.g. preparation of radiolabels of the invention)¹⁴C or³H) Isotope, in detectable dose (example)E.g., greater than about 0.5mg/kg) is administered parenterally to an animal such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and the conversion products are isolated from urine, blood, or other biological samples. These products are easily separated because they are labeled (others are separated by using antibodies that are capable of binding to the epitope that survives in the metabolite). The metabolite structure is determined in a conventional manner, for example by MS, LC/MS or NMR analysis. Analysis of metabolites is generally performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites are useful in diagnostic assays for therapeutic dosages of the compounds of the present invention as long as they are not otherwise found in vivo.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be included within the scope of the present invention.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "treatment" refers to therapeutic treatment and/or prophylactic treatment or prevention, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, remission or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. "treatment" also means extended survival compared to the expected survival if not receiving treatment. Those in need of treatment include those already with the disease or condition as well as those susceptible to the disease or condition or those to be prevented.

The phrase "therapeutically effective amount" or "effective amount" refers to the following amounts of a compound of the present invention: (i) treating or preventing a particular disease, condition, or disorder, (ii) attenuating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

The term "bioavailability" refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that represents a measure of the time (rate) and total amount (degree) of drug that reaches the systemic circulation from an administered dosage form.

RIP1 kinase inhibitors

All embodiments described herein may be combined.

The present invention provides novel compounds having the general formula I:

provided herein are compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R^AIs selected from

wherein when R is¹In the case of phenyl or benzyl, the phenyl ring is optionally substituted with 1 to 2 substituents selected from: fluorine, chlorine, cyano, C₁-C₃Alkyl, cyclopropyl, C₁-C₃Alkoxy radical, C₁-C₃Haloalkyl and C₁-C₃A haloalkoxy group;

R^2aand R^2bEach independently selected from hydrogen, deuterium, fluorine, hydroxyl, C₁-C₃Alkyl and C₁-C₃A fluoroalkyl group; provided that R is^2aAnd R^2bBoth cannot be hydroxyl; or

R¹Selected from hydrogen, deuterium, fluoro, methyl and cyano; and is

R^2aAnd R^2bTogether with the carbon atom to which they are both attached form a 4-to 6-membered heterocyclic ring or a 3-to 5-membered carbocyclic ring, each of which is optionally substituted with 1 to 2 substituents selected from: fluorine, chlorine, hydroxy, cyano, C₁-C₃Alkyl, hydroxymethyl, methoxymethyl, C₁-C₄Alkoxycarbonyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

each R⁶Independent of each otherIs selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl and C₁-C₆A haloalkoxy group; and is

The ring A and the ring B are fused to form a polycyclic ring system, wherein

p is 1 or 2, and q is 0 or 1; or p is 0 and q is 1;

provided that when R is^AIs composed of

With the further proviso that when ring B is substituted by C₁-C₆alkyl-N (R)^N)₂And phenyl substituted, and each R^NIn the case of hydrogen, the acid is,

not methyl, tert-butyl, N-ethylmorpholino or methoxyethyl.

In some embodiments of the invention, R^ASelected from:

wherein s is 0 or 1.

In some embodiments, R^AIs composed of

Wherein R is¹、R^2aAnd R^2bAs described herein.

In some embodiments of formula (I), R^AAs defined above, and ring A and ring B together (including substituents, p, q, R)^B1And R^B2) Selected from the following:

wherein

R^3aAnd R^3bThe following options are selected:

(i)R^3aand R^3bOne of which is H and the other is selected from H, D, F, Cl, OH, CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, cyclopropyl, C₁-C₄Alkoxy and C₁-C₄A haloalkoxy group;

(ii)R^3aand R^3bEach independently selected from D, F, Cl, OH, CN and methyl, with the proviso that R is^3aAnd R^3bNot all can be OH or CN; or

(iii)R^3aAnd R^3bTogether with the adjacent carbon atom form a cyclopropyl group; and is

R⁴Is selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Thioalkyl, phenyl, benzyl, CH₂-(C₃-C₆Cycloalkyl), CH₂CH₂-(C₃-C₆Cycloalkyl), CH₂- (4-to 6-membered heterocyclic group), CH₂CH₂- (4-to 6-membered heterocyclic group), 5-to 6-membered heteroaryl and CH₂- (5 to 6 membered heteroaryl); wherein when a phenyl ring is present, it may be substituted with 1 to 3 substituents selected from: halogen, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy and cyano.

In some embodiments of formula (I), R^AAs defined above, and ring A and ring B together are

Wherein

R^3aAnd R^3bThe following options are selected:

In some embodiments of formula (I), R^AAs defined above, and ring a and ring B together are selected from the following:

wherein

R^3aAnd R^3bThe following options are selected:

(iii)R^3aAnd R^3bTogether form a cyclopropyl group;

each R⁵Independently selected from H, F, Cl, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy and C₁-C₆A haloalkoxy group; and is

m is 1,2 or 3.

In some embodiments of formula (I), R^AAs defined above, and ring a and ring B together are:

wherein

Each R⁵Selected from H, F, Cl, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy and C₁-C₆A haloalkoxy group; and is

m is 0, 1,2 or 3.

In other embodiments, m is 1,2, 3.

wherein

m is 0, 1,2 or 3.

In some of the above embodiments, R^AIs composed of

And is

Selected from:

in some of the above embodiments, R^AIs composed of

And is

Selected from:

in some of the above embodiments, R^AIs composed of

And is

Selected from:

in some of the above embodiments, R^ASelected from:

in some of the above-mentioned embodimentsIn the embodiment, R^ASelected from:

in some of the above embodiments, R^ASelected from:

in some of the above embodiments, R¹Selected from hydrogen, fluorine, hydroxy, cyano, CH₂CN、C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy and 4 to 5 membered heterocyclyl; n is 0, 1,2 or 3; r^2aAnd R^2bEach independently selected from hydrogen, deuterium, fluorine, hydroxyl, C₁-C₃Alkyl radical, C₁-C₃A fluoroalkyl group; or when R is¹Hydrogen, deuterium, fluoro, methyl or cyano; r^2aAnd R^2bMay form, together with the adjacent carbon atom, a cyclopropyl group, optionally substituted with one or two substituents selected from: F. c_1-3Alkyl, hydroxy, hydroxymethyl, methoxymethyl, cyano, CO₂-C_1-3Alkyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

In some of the above embodiments, R¹Selected from hydrogen, deuterium, fluorine, hydroxy, cyano, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy, with one (R)^N)₂C substituted by N substituents₁-C₆Alkyl radical, C₁-C₆Cyanoalkyl, C₁-C₆Alkylsulfonyl, phenyl, benzyl, 4-to 6-membered heterocyclyl and 5-to 6-membered heteroaryl;

wherein when R is¹Is phenyl, benzyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₃-C₆When cycloalkyl is present, said phenyl, C₁-C₆The alkoxy or cycloalkyl ring is optionally substituted with 1 to 2 substituents selected from: fluorine, chlorine, cyano, C₁-C₃Alkyl, cyclopropyl, C₁-C₃Alkoxy radical, C₁-C₃Hydroxyalkyl radical, C₁-C₃Haloalkyl, C₁-C₆Alkoxycarbonyl group, C₁-C₃alkoxy-C₁-C₃Alkyl and C₁-C₃A haloalkoxy group;

in some of the above embodiments, R^3aAnd R^3bEach is H. In some of the above embodiments, R^3aIs H and R^3bIs D. In some of the above embodiments, R^3aIs H and R^3bIs F. In some of the above embodiments, R^3aIs H and R^3bIs Cl. In some of the above embodiments, R^3aAnd R^3bEach is D. In some of the above embodiments, R^3aAnd R^3bEach is F. In some of the above embodiments, R^3aAnd R^3bEach is Cl. In some of the above embodiments, R^3aAnd R^3bEach is methyl. In some of the above embodiments, R^3aIs methyl and R^3bIs F. In some of the above embodiments, R^3aIs methyl and R^3bIs Cl. In some of the above embodiments, R^3aIs methyl and R^3bIs OH. In some of the above embodiments, R^3aIs methyl and R^3bIs CN.

In some of the above embodiments, R⁴Is phenyl. In some embodiments, R⁴Is mono-or difluorophenyl. In some embodiments, R⁴Is a mono-fluorophenyl group. In some embodiments, R⁴Is mono or dichlorophenyl. In some embodiments, R⁴Is monochlorophenyl.

In some of the above embodiments, R⁵Selected from H, F, Cl, CH₃、CH₂CH₃、OCH₃、CF₃、OCF₃、CF₂H and OCF₂H. In some of the above embodiments, R⁵Is H. In some of the above embodiments, R⁵Is F. In some of the above embodiments, R⁵Is Cl. In some of the above embodiments, R⁵Is CH₃. In some of the above embodiments, R⁵Is CF₃。

In some of the above embodiments, each R is^NIndependently selected from H and C₁-C₆An alkyl group. In some embodiments, each R is^NIs C₁-C₄An alkyl group. In some embodiments, each R is^NIs methyl.

In some of the above embodiments, n is 0. In some of the above embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some of the above embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some of the above embodiments, m is 1and R⁵Is F. In some embodiments, m is 2 and R⁵Is F. In some of the above embodiments, m is 1and R⁵Is Cl. In some embodiments, m is 2 and R⁵Is Cl.

In some of the above embodiments, each R is⁶Independently selected from hydrogen and C₁-C₃An alkyl group. In some of the above embodiments, each R is⁶Is hydrogen or methyl.

In some of the above embodiments, R⁶Independently selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Cyanoalkyl, C₁-C₃Alkylcarbonyl group, C₁-C₃Methanesulfonyl group, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, formyl, C₁-C₆Haloalkoxy, cyano, 1-methyl-pyrazol-4-yl, and pyrimidinyl.

This paper also providesA compound selected from the compounds of table 1 below or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a method of treating a subject with RIP1K (including as described herein) having a K of less than 100nM in a biochemical or cell-based assay (including as described herein)_iThe compound of table 1. In another embodiment, the compound of table 1 has a K of less than 50nM in a RIP1K biochemical or cell-based assay (including as described herein)_i. In yet another embodiment, the compound of table 1 has a K of less than 25nM in a RIP1K biochemical or cell-based assay (including as described herein)_i. In yet another embodiment, the compound of table 1 has a K of less than 10nM in a RIP1K biochemical or cell-based assay (including as described herein)_i。

In some embodiments, provided herein are single stereoisomers of the compounds of table 1, characterized by reference to chiral separation and isolation thereof (e.g., by chiral SFC as described in the examples).

In some embodiments, provided herein are pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as described in any one of the above embodiments, and one or more pharmaceutically acceptable carriers or excipients. Particular embodiments include pharmaceutical compositions suitable for oral delivery.

Also provided herein are oral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described in any one of the embodiments above, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

In some embodiments, provided herein is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described in any one of the above embodiments, in the treatment of neurodegenerative diseases and disorders. In some embodiments, the disease or disorder to be treated is synucleinopathic disease (synucleinopathic), such as parkinson's disease, dementia with lewy bodies, multiple system atrophy, parkinsonian stacking syndrome. In some embodiments, the disease or disorder to be treated is a tauopathy (tauopathy), such as alzheimer's disease and frontotemporal dementia. In some embodiments, the disease or disorder to be treated is a demyelinating disease, e.g., multiple sclerosis.

In some embodiments, the diseases and disorders to be treated are other neurodegenerative diseases, such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, huntington's disease, ischemia, and stroke. Other exemplary neurodegenerative diseases to be treated as provided herein include, but are not limited to, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, adrenocortical degeneration, and demyelinating diseases.

In some embodiments, the disease or disorder to be treated is alzheimer's disease. In some embodiments, the disease or disorder to be treated is parkinson's disease. In some embodiments, the disease or disorder to be treated is huntington's disease. In some embodiments, the disease or disorder to be treated is multiple sclerosis. In some embodiments, the disease or disorder to be treated is Amyotrophic Lateral Sclerosis (ALS). In some embodiments, the disease or disorder to be treated is Spinal Muscular Atrophy (SMA).

In some embodiments, the disease or disorder to be treated is selected from inflammatory bowel disease (including crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis, Systemic Lupus Erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver injury/disease (non-alcoholic steatohepatitis, autoimmune hepatitis autoimmune liver disease, Primary Sclerosing Cholangitis (PSC), acetaminophen toxicity, hepatotoxicity, kidney damage/injury (nephritis, kidney transplant, surgery, administration of nephrotoxic drugs such as atopic, Acute Kidney Injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, rejection, reperfusion injury of solid organs, ischemic disease, cerebrovascular inflammation syndrome(s), cerebrovascular inflammation syndrome (sacodynopathy), systemic lipodiesterase, acute renal injury (akinesia), acute celiosis), celiosis, and juvenile-induced lipodystrophy, systemic lipodystrophy, systemic sclerosis (e-induced lipodystrophy), systemic sclerosis), mucose deficiency, atherosclerosis, neuroblastoma-induced sclerosis (piceidosis), systemic sclerosis, mucositis, neuroblastoma-induced sclerosis, leukemia, systemic sclerosis, neuroblastoma-induced sclerosis (leukemia, leukemia-induced lipodystrophy, leukemia-induced lipodystrophy, leukemia-induced lipodystrophy, leukemia, obesity-induced lipodystrophy, leukemia, systemic sclerosis, and systemic sclerosis (leukemia, diabetes mellitus, systemic sclerosis, diabetes mellitus, systemic sclerosis, and other diseases (including lipodystrophy-induced lipodystrophy, systemic sclerosis, and other diseases (including lipodystrophy-induced sclerosis, systemic sclerosis, and other diseases (e-induced lipodystrophy-induced sclerosis, systemic sclerosis, and other diseases (e-induced sclerosis, and other diseases (including lipodystrophy-induced sclerosis, systemic sclerosis, and other diseases (including lipodystrophy-induced sclerosis, systemic sclerosis, and systemic sclerosis, and systemic sclerosis, and systemic sclerosis, adephagitis, and systemic sclerosis, and systemic sclerosis, adelomatosis (including lipodystrophy-induced lipodystrophy-.

In some embodiments, the disease or disorder to be treated is inflammatory bowel disease. In some embodiments, the disease or disorder to be treated is crohn's disease. In some embodiments, the disease or disorder to be treated is ulcerative colitis. In some embodiments, the disease or disorder to be treated is glaucoma. In some embodiments, the disease or disorder to be treated is psoriasis. In some embodiments, the disease or disorder to be treated is rheumatoid arthritis. In some embodiments, the disease or disorder to be treated is spondyloarthritis. In some embodiments, the disease or disorder to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or condition to be treated is osteoarthritis.

In some embodiments, provided herein are methods of treating or preventing a disease or disorder with a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and/or necrotic apoptosis. In some embodiments, the disease or disorder is selected from the specific diseases and disorders listed herein.

In some embodiments, provided herein are methods of inhibiting RIP1 kinase activity by contacting a cell with a compound of formula I, or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions and administration

Provided herein are pharmaceutical compositions or medicaments containing a compound of the invention (or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, isotope, pharmaceutically acceptable salt or prodrug thereof) and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, a compound of formula I may be formulated for galenic administration by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosages and concentrations employed) at ambient temperature at a suitable pH and desired purity. The pH of the formulation depends primarily on the particular use and concentration of the compound, but preferably ranges from about 3 to about 8. In one example, the compound of formula I is formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula I are sterile. The compounds may be stored, for example, in the form of solid or amorphous compositions, lyophilized formulations, or aqueous solutions.

The compositions may be formulated, dosed, and administered in a manner consistent with good medical practice. Factors considered herein include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause, the location of drug delivery, the method of administration, the administration regimen, and other factors known to medical practitioners. In some embodiments, an "effective amount" of the compound to be administered will be determined by such considerations, which is the minimum amount necessary to inhibit RIP1 kinase activity to provide a therapeutic effect in the mammal being treated. In addition, the effective amount may be less than an amount that is toxic to normal cells or the mammal as a whole.

In one example, a pharmaceutically effective amount of a compound of the invention administered intravenously or parenterally will be about 0.1 to 100mg/kg of patient body weight per dose, or about 0.1 to 20mg/kg of patient body weight per day, or about 0.3 to 15 mg/kg/day.

In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 1 to about 1000mg (e.g., 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 40mg, 50mg, 100mg, 200mg, 250mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg or 1000mg) of a compound of the invention. The daily dose is in some embodiments administered as a single daily dose or in divided doses administered from two to six times a day, or in a sustained release form. For a 70kg adult, the total daily dose will generally be from about 7mg to about 1,400 mg. The dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In some embodiments, a low dose of a compound of the invention is administered to provide a therapeutic benefit while minimizing or preventing adverse effects.

The compounds of the invention may be administered in any suitable manner including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In a specific embodiment, the compound of formula I is administered orally. In other embodiments, the compound of formula I is administered intravenously.

The compounds of the invention may be administered in any conventional form of administration such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional ingredients of pharmaceutical formulations such as diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are known to those skilled in the art and are described in detail, for example, in Ansel, Howard c. et al, Ansel's pharmaceutical Dosage Forms and Drug Delivery systems, philiadelphia: lippincott, Williams & Wilkins, 2004; gennaro, Alfonso r. et al, Remington: the scientific and Practice of pharmacy Philadelphia: lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.handbook of Pharmaceutical excipients Chicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, diluents, and other known additives to provide an elegant appearance of the drug (drug) (i.e., a compound of the present invention or pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., medicament).

Suitable carriers, diluents and excipients are known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the compounds of the present invention are to be employed. The solvent is typically selected based on a solvent recognized by those skilled in the art as safe for administration to a mammal (GRAS). Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulations may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants and other known additives to provide an elegant appearance of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., medicament).

Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; parabens such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or a non-ionic surfactant such as TWEENTM, PLURONICSTM, or polyethylene glycol (PEG). The active pharmaceutical ingredients of the present invention (e.g. compounds of formula I or embodiments thereof) may also be encapsulated in microcapsules such as hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacylate) microcapsules, colloidal drug delivery systems (e.g. liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions, for example prepared by coacervation techniques or by interfacial polymerization, respectively. Such techniques are disclosed in Remington: the Science and practice of Pharmacy: remington the Science and Practice of Pharmacy(2005)21^stEdition，Lippincott Williams&Wilkins，Philidelphia，PA。

Sustained release formulations of the compounds of the invention (e.g., compounds of formula I or embodiments thereof) may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and ethyl-gamma-L-glutamate (Sidman et al, Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al, J.biomed.Mater.Res.15:167, 1981), degradable lactic acid-glycolic acid copolymers such as LUPRONDEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D- (-) -3-hydroxybutyric acid (EP133, 988A). Sustained release compositions also include liposome-entrapped compounds, which can be prepared by methods known per se (Epstein et al, Proc. Natl. Acad. Sci. U.S. A.82:3688, 1985; Hwang et al, Proc. Natl. Acad. Sci. U.S. A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP102,324A). Typically, liposomes are of the small (about 200-800 angstroms) monolayer type, where the lipid content is greater than about 30 mol% cholesterol, the selected ratio being adjusted for optimal therapy.

In one example, a compound of formula I or embodiments thereof may be formulated for administration in galenic form by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosages and concentrations employed) at ambient temperature, at an appropriate pH, and in the desired purity. The pH of the formulation depends primarily on the particular use and compound concentration, but is preferably from about 3 to about 8. In one example, a compound of formula I (or embodiments thereof) is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula I or embodiments thereof is sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

Examples of suitable oral dosage forms provided herein are tablets containing from about 1 to about 500mg (e.g., about 1mg, 5mg, 10mg, 25mg, 30mg, 50mg, 80mg, 100mg, 150mg, 250mg, 300mg, and 500mg) of a compound of the invention admixed with appropriate amounts of lactose anhydrous, croscarmellose sodium, polyvinylpyrrolidone (PVP) K30, and magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition is dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment.

The formulations of the compounds of the present invention (e.g., compounds of formula I or embodiments thereof) may be in the form of sterile injectable formulations, for example, sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol, or as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any mixed fixed oil may be employed for this purpose, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, time-release formulations intended for oral administration to humans may contain from about 1 to 1000mg of the active material in admixture with a suitable and convenient amount of carrier material which may comprise from about 5 to about 95% by weight of the total composition. Pharmaceutical compositions can be prepared to provide readily determinable amounts for administration. For example, an aqueous solution for intravenous infusion may contain about 3 to 500 μ g of active ingredient per mL of solution so that an appropriate volume infusion can be performed at a rate of about 30 mL/hr.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, pharmaceutical compositions are included comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Certain embodiments of the present invention provide compounds of formula I (or embodiments thereof) that cross the blood-brain barrier when the binding target is located in the brain. In these embodiments, the compounds provided herein exhibit sufficient brain penetration as potential therapeutic agents in neurological diseases. In some embodiments, the free brain/plasma ratio (B) is measured by assessing the free brain/plasma ratio in an in vivo pharmacokinetic study in rodents_u/P_u) Or by other methods known to those skilled in the art (see, e.g., Liu, x. et al, j.pharmacol. exp. therap., 325:349-56, 2008).

Certain neurological diseases are associated with increased blood brain barrier permeability, so that the compounds of formula I (or embodiments thereof) can be readily introduced into the brain. While the blood-brain barrier remains intact, there are several prior art known methods for transporting molecules across the blood-brain barrier, including but not limited to physical methods, lipid-based methods, and receptor-based, and channel-based methods. Physical methods of crossing the blood-brain barrier for compounds of formula I (or embodiments thereof) include, but are not limited to, completely bypassing the blood-brain barrier, or by forming an opening in the blood-brain barrier.

Bypass methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al, Gene therapy 9:398-406, 200), interstitial infusion/convection current augmentationStrong delivery (see, e.g., Bobo et al, Proc. Natl. Acad. Sci. U.S.A.91:2076-^TM，Guildford。

Methods of forming openings in barriers include, but are not limited to, sonication (see, e.g., U.S. patent publication No. 2002/0038086), osmotic pressure (e.g., by application of hypertonic mannitol Neuwelt, e.a., immunization of the Blood-Brain Barrier and its management, Volumes1and 2, Plenum Press, n.y., 1989)), and by permeabilization of, e.g., bradykinin or permeabilizing agent a-7 (see, e.g., U.S. patent nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of crossing the blood-brain barrier of a compound of formula I (or embodiments thereof) include, but are not limited to, encapsulating a compound of formula I or formula I-I (or embodiments thereof) in a liposome coupled to an antibody-binding fragment that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. patent publication No. 2002/0025313), and encapsulating a compound of formula I (or embodiments thereof) in a low density lipoprotein particle (see, e.g., U.S. patent publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. patent publication No. 2004/0131692).

Receptor-based, channel-by-channel methods of crossing the blood-brain barrier of compounds of formula I (or embodiments thereof) include, but are not limited to, the use of glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. patent publication nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. patent publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. patent publication No. 2003/0073713); coating a compound of formula I or I-I (or embodiments thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. patent publication No. 2003/0129186), and cationizing antibodies (see, e.g., U.S. patent No. 5,004,697).

For intracerebral use, in certain embodiments, the compound may be administered continuously by infusion into a fluid reservoir of the CNS, although a bolus injection may be acceptable. The inhibitor may be administered into the ventricles of the brain, or introduced into the CNS or spinal fluid. Administration may be by use of an indwelling catheter and a continuous administration device such as a pump, or may be by implantation of a slow release carrier, for example, in the brain. More specifically, the inhibitor may be injected through a chronically implanted cannula or chronically infused with the aid of an osmotic mini-pump. Subcutaneous pumps are available which deliver proteins to the ventricles of the brain via a small tube. Highly complex pumps can be refilled through the skin and their delivery rate can be set without surgical intervention. Examples of suitable administration regimens and delivery systems involving subcutaneous pump devices or continuous intraventricular infusion via fully implanted drug delivery systems are those for administering dopamine, dopamine agonists and cholinergic agonists to alzheimer's patients and animal models of parkinson's disease, such as Harbaugh, j.neural trans.suppl.24: 271, 1987; and DeYebrenes et al, Mov.Disord.2: 143, 1987.

Indications and treatment methods

The compounds of the invention inhibit RIP1 kinase activity. Accordingly, the compounds of the present invention are useful for treating diseases and conditions mediated by this pathway and associated with inflammation and/or necrotic cell death.

In some embodiments, the disease or disorder to be treated is a neurodegenerative disease or disorder. In some embodiments, the disease or disorder to be treated is a synucleinopathy, such as parkinson's disease, dementia with lewy bodies, multiple system atrophy, parkinsonian stacking syndrome. In some embodiments, the diseases and disorders to be treated are tauopathies, such as alzheimer's disease and frontotemporal dementia. In some embodiments, the disease or disorder to be treated is a demyelinating disease, e.g., multiple sclerosis.

In some embodiments, the disease or disorder to be treated is selected from inflammatory bowel disease (including crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis, Systemic Lupus Erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver injury/disease (non-alcoholic steatohepatitis, autoimmune hepatitis hepatobiliary disease, Primary Sclerosing Cholangitis (PSC), acetaminophen toxicity, hepatotoxic drugs such as cisplatin administration, Acute Kidney Injury (AKI), chyle, autoimmune thrombocytopenic purpura, transplant rejection, ischemia/injury (fever, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin), acute kidney injury (akinesis), acute kidney storage lesion (akinesis), atherosclerosis-induced lipodystrophy), systemic sclerosis, lipodystrophy-induced lipodystrophy, systemic sclerosis, neuroblastoma, systemic sclerosis.

In some embodiments, the methods of treatment provided herein are treating one or more symptoms of a disease or disorder listed above.

Also provided herein are uses of the compounds of the invention in therapy. In some embodiments, provided herein is the use of a compound of the invention for the treatment or prevention of the diseases and disorders described above. Also provided herein is the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of the diseases and conditions described above.

Also provided herein is a method of treating a disease or disorder as provided above in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the mammal is a human.

Also provided herein is a method of treating a symptom of a disease or disorder selected from Irritable Bowel Disease (IBD), Irritable Bowel Syndrome (IBS), crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of the kidney, liver and lung, cisplatin-induced kidney injury, sepsis, Systemic Inflammatory Response Syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, Acute Respiratory Distress Syndrome (ARDS), and Chronic Obstructive Pulmonary Disease (COPD) in a mammal in need thereof, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a disease or condition selected from those provided above in a human patient in need of such treatment, wherein the method comprises orally administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as an orally acceptable pharmaceutical composition.

Combination therapy

The compounds of the present invention may be combined with one or more other compounds of the present invention or one or more other therapeutic agents in any combination thereof for the treatment of the diseases and conditions provided herein. For example, the compounds of the present invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents known to be useful in the treatment of a disease or condition selected from those described above.

As used herein, "combination" refers to any mixture or permutation (permutation) of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agents. Unless the context indicates otherwise, "combining" may include simultaneous or sequential delivery of a compound of the invention and one or more therapeutic agents. Unless the context indicates otherwise, "combination" may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context indicates otherwise, "combination" may include the route of administration of a compound of the invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include formulation of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

In some embodiments, the compounds provided herein may be combined with another therapeutically active agent described in WO 2016/027253, the contents of which are incorporated herein by reference in their entirety. In such embodiments, the compound that inhibits RIP1 kinase in the combination described in WO 2016/027253 is replaced by a compound of formula I of the present disclosure.

In some embodiments, the compounds provided herein may be combined with DLK inhibitors to treat neurodegenerative diseases and disorders, such as those listed elsewhere herein, including, but not limited to, the following: parkinson's disease, dementia with lewy bodies, multiple system atrophy, parkinsonism plus syndrome, alzheimer's disease, frontotemporal dementia, demyelinating diseases such as multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, genetic muscular atrophy, peripheral neuropathy, progressive supranuclear palsy and adrenocortical degeneration. DLK inhibitors are described, for example, in WO2013/174780, WO 2014/177524, WO 2014/177060, WO2014/111496, WO 2015/091889 and WO 2016/142310.

Examples

The invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention.

These examples are intended to provide guidance to those skilled in the art in making and using the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention have been described, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

The chemical reactions in the examples can be readily adapted to prepare many other compounds of the invention, and alternative methods of preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds of the invention may be successfully carried out by modifications apparent to those skilled in the art, for example, by appropriate protection of interfering groups, by the use of other suitable reagents known in the art in addition to those described, and/or by routine modification of reaction conditions.

In the following examples, all temperatures are expressed in degrees celsius unless otherwise indicated. Commercial reagents were purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and used without further purification unless otherwise stated. The reactions listed below are generally carried out under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise indicated) in anhydrous solvents, and the reaction flasks are usually equipped with rubber septa to introduce substrates and reagents via syringe. The glassware is dried and/or heat dried. In deuterated CDCl₃、d₆-DMSO、CH₃OD or d₆Acetone solvent solution (reported in ppm) obtained using Trimethylsilane (TMS) or residual non-deuterated solvent peak as reference standard¹H NMR spectrum. When peak multiplicities are reported, the following abbreviations are used: s (Single peak)D (doublet), t (triplet), q (quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt (doublet of triplets). coupling constants, when given, are reported in Hz (hertz).

All abbreviations used to describe reagents, reaction conditions or devices are intended to be consistent with the definitions set forth in the following list of abbreviations. The chemical names of the individual compounds of the invention are typically obtained using the structural naming features of the ChemDraw naming program.

Abbreviations

ACN acetonitrile

Boc tert-butoxycarbonyl

DAST diethylaminosulfur trifluoride

DCE 1, 2-dichloroethane

DCM dichloromethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPH 2, 2-diphenyl-1-picrylhydrazino

HPLC high performance liquid chromatography

LCMS liquid chromatography mass spectrometry

PCC pyridinium chlorochromate

RP inverse

RT or R_TRetention time

SEM 2- (trimethylsilyl) ethoxymethyl

SFC supercritical fluid chromatography

TBDMS tert-butyldimethylsilyl group

TFA trifluoroacetic acid

THF tetrahydrofuran

Synthetic schemes

In addition to the specific synthetic methods of the following examples, other compounds of the invention can be prepared, for example, according to the following synthetic schemes.

Schemes 1-4 illustrate the preparation of chemical intermediates provided in the examples herein.

Scheme 1

Scheme 2

Other B-ring diversity of compounds of formula I were prepared according to scheme 3 using a variety of nucleophiles (including but not limited to halide and cyanide sources):

scheme 3

A gem-dimethyl B ring substituted compound of formula I was prepared according to scheme 4:

scheme 4

The following intermediates used in the following examples were prepared according to the procedure described in WO 2017/004500 (the entire contents of which are incorporated herein by reference):

certain compounds of formula I were then prepared according to scheme 5 using the following exemplary reaction:

scheme 5

Exemplary preparation of monofluorinated intermediates:

step 1: 3, 5-dibromo-1- (tetrahydro-2H-pyran-2-yl) -1H-1,2, 4-triazole

To a solution of 3, 5-dibromo-1 h-1,2, 4-triazole (150.0g, 661.2mmol) in tetrahydrofuran (1500mL) was slowly added p-toluenesulfonic acid (17.1g, 99.2mmol) followed by 3, 4-dihydro-2 h-pyran (166.9g, 1983.6mmol) at 0 ℃. After addition, the reaction mixture was heated at 70 ℃ for 3h and concentrated under reduced pressure. The residue was poured into water (500mL) and adjusted to pH 9 by addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was washed with methanol (2 × 50mL) and dried under reduced pressure to give crude 3, 5-dibromo-1-tetrahydropyran-2-yl-1, 2, 4-triazole (155g, 75%) as a white solid.¹H NMR(400MHz，CDCl₃)δ5.49–5.46(m，1H)，4.12–3.99(m，1H)，3.72–3.61(m，1H)，2.38–2.26(m，1H)，2.18–2.07(m，1H)，1.98–1.90(m，1H)，1.78–1.60(m，3H)。

Step 2: 1-phenylbut-3-en-1-ol

To a cooled (0 ℃ C.) solution of benzaldehyde (130g, 1.23mol) in tetrahydrofuran (1000mL) was added allyl magnesium chloride (2M in THF, 858mL, 1.72mol) over 30 minutes. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched by addition of saturated aqueous ammonium chloride (1000mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate/petroleum ether) to give 1-phenylbut-3-en-1-ol as a pale yellow oil (140g, 77%).¹H NMR(400MHz，CDCl₃)δ7.37–7.34(m，4H)，7.29–7.26(m，1H)，5.83–5.75(m，1H)，5.21–5.08(m，2H)，4.76–4.69(m，1H)，2.55–2.45(m，2H)，2.12(d，J＝2.8Hz，1H)。

And step 3: tert-butyldimethyl ((1-phenylbut-3-en-1-yl) oxy) silane

To a stirred solution of 1-phenyl-3-buten-1-ol (29.0g, 195.7mmol) in dichloromethane (400mL) was added imidazole (27.0g, 391.6mmol) and tert-butyldimethylsilyl chloride (39.0g, 254.4 mmol). After addition, the reaction mixture was stirred at 25 ℃ for 16h, then quenched by the addition of water (200 mL). The mixture was extracted with dichloromethane (2 × 200 mL). The combined organic layers were washed with brine (100mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) to give tert-butyl-dimethyl- (1-phenylbut-3-enyloxy) silane (43.0g, 84%) as a colorless oil, which was used as such in the next step.

And 4, step 4: 3- ((tert-butyldimethylsilyl) oxy) -3-phenylpropionaldehyde

To a solution of tert-butyl-dimethyl- (1-phenylbut-3-enyloxy) silane (50.0g, 190.5mmol) in tetrahydrofuran/water (600mL, 1:1) was added osmium tetroxide (968mg, 3.8 mmol). After stirring for 30 minutes at 15 ℃ sodium periodate (163g, 762.0mmol) was added in small portions over 2 h. The resulting mixture was stirred at 30 ℃ for an additional 2h, then quenched by the addition of cold saturated aqueous sodium thiosulfate solution (500 mL). The mixture was stirred for 30min, then extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with water (200mL), brine (200mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate/petroleum ether) to give 3- [ tert-butyl (dimethyl) silyl group as a yellow oil]Oxy-3-phenyl-propanal (33.0g, 65%).¹H NMR(400MHz，CDCl₃)δ9.94(t，J＝2.4Hz，1H)，7.48(d，J＝4.2Hz，4H)，7.44–7.39(m，1H)，5.37–5.34(m，1H)，2.99–2.97(m，1H)，2.80–2.75(m，1H)，1.01(s，9H)，0.19(s，3H)，0.00(s，3H)。

And 5: 1- (3-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-1,2, 4-triazol-5-yl) -3- ((tert-butyldimethylsilyl) oxy) -3-phenylpropan-1-ol

In N₂To a cooled (-78 ℃ C.) solution of 3, 5-dibromo-1-tetrahydropyran-2-yl-1, 2, 4-triazole (39.0g, 125.4mmol) in tetrahydrofuran (400mL) was added n-butyllithium (2.5M in hexane, 55.0mL, 137.5mmol) dropwise under an atmosphere. The mixture was stirred at-78 ℃ for 30 minutes and then 3- [ tert-butyl ] was added dropwiseButyl (dimethyl) silyl]A solution of oxy-3-phenyl-propanal (33.0g, 124.2mmol) in tetrahydrofuran (50 mL). After addition, the mixture was stirred at-78 ℃ for 1.5h and then quenched by addition of saturated aqueous ammonium chloride (500 mL). The resulting mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 mesh, 200 mesh, 0 to 5% ethyl acetate/petroleum ether) to give 1- (3-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-1,2, 4-triazol-5-yl) -3- ((tert-butyldimethylsilyl) oxy) -3-phenylpropan-1-ol as a pale yellow oil (50.0g, 80%).

Step 6: trans-2-bromo-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-7-ol

To a stirred solution of 1- (3-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-1,2, 4-triazol-5-yl) -3- ((tert-butyldimethylsilyl) oxy) -3-phenylpropan-1-ol (50.0g, 100.7mmol) in dichloromethane (150mL) was slowly added trifluoroacetic acid (150 mL). The resulting mixture was heated at 50 ℃ for 2h and then concentrated under reduced pressure. The residue was adjusted to pH 9 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with water (100mL), brine (100mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 32% ethyl acetate/petroleum ether) to give trans-2-bromo-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a yellow solid][1,2,4]Triazol-7-ol (5.5g, 20%) (a second fraction (8.5g, 30%) was also obtained as a 4:3 mixture of trans/cis products).¹H NMR(400MHz，CDCl₃)δ7.46–7.32(m，3H)，7.15(d，J＝7.6Hz，2H)，5.65(t，J＝6.6Hz，1H)，5.50(br s，1H)，5.45(d，J＝6.4Hz，1H)，3.19–3.11(m，1H)，3.01–2.92(m，1H)。LCMS RT＝0.682min，m/z＝279.8[M+H]⁺. LCMS (5 to 95% aqueous acetonitrile + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.682 min, ESI + found [ M + H ]]＝279.8。

And 7: (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5R,7R) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a stirred solution of trans-2-bromo-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-7-ol (3.0g, 10.71mmol) in dichloromethane (60mL) was slowly added diethylaminosulfur trifluoride (7.8g, 48.19mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5h, then added to a stirred saturated aqueous sodium bicarbonate solution (100mL) at 0 ℃. The mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with water (100mL), brine (100mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 mesh, 0 to 20% ethyl acetate/petroleum ether) to give racemic cis-2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (1.5g, 49%) as a pale yellow solid and racemic trans-2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (650mg, 21%) as a white solid.

Cis-2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole:¹H NMR(400MHz，CDCl₃)δ7.31–7.24(m，3H)，7.17–7.07(m，2H)，5.97–5.77(m，1H)，5.37–5.27(m，1H)，3.52–3.37(m，1H)，2.84–2.70(m，1H)。LCMS R_T＝0.632min，m/z＝281.9[M+H]⁺. LCMS (5 to 95% aqueous acetonitrile + 0.03% trifluoroacetic acid for 1.5mins) retention time 0.632min, ESI + found [ M + H ]]＝281.9。

Trans-2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole:¹H NMR(400MHz，CDCl₃)δ7.58–7.29(m，3H)，7.24–7.05(m，2H)，6.14–5.93(m，1H)，5.70–5.65(m，1H)，3.41–3.25(m，1H)，3.04–2.87(m，1H)。

the racemic cis-species was further separated by chiral SFC to give any of the named:

(5R,7R) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (peak 1, retention time 2.963 min) as a white solid (350mg, 44%).

(5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (peak 2, retention time 3.174 min) as a white solid (350mg, 44%).

SFC conditions: column: chiralpak AD-3150 × 4.6mm i.d., 3um mobile phase: a: CO2₂B: ethanol (0.05% DEA) gradient: 5% to 40% B and hold 40% for 2.5 minutes in 5 minutes, then 5% B for 2.5 minutes flow rate: 2.5 mL/min.

Example 1: method 1

Cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propan-1-ol

To 1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazol-2-yl]To a cooled solution of propan-1-one (21mg, 0.08mmol) in methanol (5mL) was added sodium borohydride (28mg, 0.73mmol) in one portion. The mixture was stirred at 0 ℃ for 1h, then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% aqueous hydrochloric acid) to give any of the named cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a colorless oil][1,2,4]Triazol-2-yl]Propan-1-ol (17mg, 71%).¹H NMR(400MHz，CD₃OD)δ7.40–7.33(m，3H)，7.25–7.22(m，2H)，6.16–6.13(m，0.5H)，6.02–5.98(m，0.5H)，5.56–5.52(m，1H)，4.65–4.61(m，1H)，3.75–3.67(m，1H)，2.81–2.74(m，1H)，1.93–1.82(m，2H),0.94–0.89(m，3H)。LCMS R_T0.762 min, 262.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.762 min, ESI + observed [ M + H ] ═ 262.0.

Example 2: method 2

Cis-2- (1, 1-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To 1- (cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 ℃ under a nitrogen atmosphere][1,2,4]To a solution of triazol-2-yl) propan-1-one (40mg, 0.15mmol) in dichloromethane (10mL) was added diethylaminosulfur trifluoride (50mg, 0.31 mmol). After addition, the mixture was stirred at 25 ℃ for 2h and quenched by the slow addition of saturated aqueous sodium bicarbonate solution (10 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give any named cis-2- (1, 1-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (17mg, 40%).¹H NMR(400MHz，CD₃OD)δ7.41–7.23(m，5H)，6.16–6.00(m，1H)，5.58(s，1H)，3.78–3.69(m，1H)，2.80–2.77(m，1H)，2.31–2.25(m，2H)，1.02(t，J＝7.6Hz，3H)。LCMS R_T0.859 min, M/z 281.9[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 0.859 minutes, ESI + observed [ M + H ] ═ 281.9.

Example 3: method 3

Cis-7-fluoro-2- (1-fluoropropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: 1- (cis-5-fluoro-7-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propan-1-ol

1- (cis-5-) at 0 DEG CFluoro-7-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]To a solution of triazol-2-yl) propan-1-one (120mg, 0.46mmol) in methanol (10mL) was added sodium borohydride (21mg, 0.56 mmol). The resulting solution was stirred at 0 ℃ for 1h, then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure to give crude 1- (cis-5-fluoro-7-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl) propan-1-ol (90mg, 74%). LCMS R_T0.548 min, 262.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.548 min, ESI + observed [ M + H ] ═ 262.0.

Step 2: cis- (5S,7S) -7-fluoro-2- (1-fluoropropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

To 1- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at-78 ℃ under a nitrogen atmosphere][1,2,4]To a solution of triazol-2-yl) propan-1-ol (90mg, 0.34mmol) in dichloromethane (15mL) was added dropwise diethylaminosulfur trifluoride (0.05mL, 0.36 mmol). After addition, the mixture was stirred at-78 ℃ for 2h and quenched by the slow addition of saturated aqueous sodium bicarbonate solution (10 mL). The mixture was then extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% aqueous ammonia hydroxide) to give any of the named cis- (5S,7S) -7-fluoro-2- (1-fluoropropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (28mg, 30%).¹H NMR(400MHz，CD₃OD)δ7.40–7.21(m，5H)，6.14–5.98(m，1H)，5.56–5.34(m，2H)，3.77–3.67(m，1H)，2.81–2.70(m，1H)，2.13–2.03(m，2H)，0.98(t，J＝7.6Hz，3H)。LCMS R_T0.820 min, M/z 263.9[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 0.820 minutes, ESI + observed [ M + H ] ═ 263.9.

Example 4: method 4

Cis- (5S,7S) -2,2, 2-trifluoro-1- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) ethanol

Step 1: cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carbaldehyde

Cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at-78 DEG C][1,2,4]A mixture of triazole-2-carboxylic acid ethyl ester (800mg, 2.91mmol) in dichloromethane (30mL) was added diisobutylaluminum hydride (1.0M in toluene, 4.36mL, 4.36mmol) dropwise. After the addition, the reaction was stirred at the same temperature for 2h, then quenched by the slow addition of sodium sulfate decahydrate (3 g). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate/petroleum ether) to give cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole-2-carbaldehyde (520mg, 77%).¹H NMR(400MHz，CDCl₃)δ9.97(s，1H)，7.43–7.26(m，5H)，6.14–5.96(m，1H)，5.54–5.51(m，1H)，3.73–3.63(m，1H)，2.99–2.95(m，1H)。

Step 2: cis- (5S,7S) -2,2, 2-trifluoro-1- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazol-2-yl) ethanol

Cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole-2-carbaldehyde (50mg, 0.22mmol) anda mixture of cesium fluoride (65mg, 0.43mmol) in (trifluoromethyl) trimethylsilane (62mg, 0.43mmol) was stirred at 25 deg.C for 12h, then diluted with added methanol (5 mL). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% aqueous HCl) to give any named cis- (5S,7S) -2,2, 2-trifluoro-1- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl) ethanol (6.3mg, 9%).¹H NMR(400MHz，CDCl₃)δ7.43–7.36(m，3H)，7.25–7.22(m，2H)，6.08–5.95(m，1H)，5.49–5.45(m，1H)，5.16–5.13(m，1H)，3.68–3.63(m，1H)，3.10–2.88(m，2H)。LCMS R_T0.768 min, 301.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.768 min, ESI + observed [ M + H ] ═ 301.9.

Example 5: method 5

Cis- (5S,7S) -2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

Cyclopropyl- (cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]A mixture of triazol-2-yl) methanone (200mg, 0.74mmol) and diethylaminosulfur trifluoride (0.2mL, 1.47mmol) was stirred at 50 ℃ under nitrogen for 72 h. The mixture was slowly added to a stirred saturated aqueous sodium bicarbonate solution (20mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give the arbitrarily specified cis-2- [ cyclopropyl (difluoro) methyl group as a yellow solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (13mg, 6%).¹H NMR(400MHz，CD₃OD)δ7.43–7.24(m，5H)，6.16–6.14(m，0.5H)，6.02–6.00(m，0.5H)，5.60–5.56(m，1H)，3.77–3.69(m，1H)，2.81–2.77(m，1H)，1.79–1.74(m，1H)，0.73–0.69(m，4H)。LCMS R_T0.900 min, 293.9[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 0.900 minutes, ESI + observed [ M + H ] ═ 293.9.

Example 6: method 6

Cis- (5S,7S) -2- (1-fluoro-1-methyl-propyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: 2- (cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) butan-2-ol

To 1- [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at-78 ℃ under a nitrogen atmosphere][1,2,4]Triazol-2-yl]To a solution of propan-1-one (230mg, 0.89mmol) in tetrahydrofuran (30mL) was added methylmagnesium bromide (3.0N in tetrahydrofuran, 1.18mL, 3.55 mmol). After addition, the mixture was stirred at-78 ℃ for 1h, then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 27-57%/0.05% aqueous hydrochloric acid) to give 2- [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Butan-2-ol (160mg, 65%).¹H NMR(400MHz，CD₃OD)δ7.45–7.29(m，5H)，6.31–6.28(m，0.5H)，6.17–6.14(m，0.5H)，5.67–5.62(m，1H)，3.87–3.73(m，1H)，2.92–2.78(m，1H)，1.97–1.82(m，2H)，1.56–1.55(m，3H)，0.89–0.82(m，3H)。LCMS R_T0.571 min, M/z 276.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.571 min, ESI + observed [ M + H ] ═ 276.1.

Step 2: cis-2- (1-fluoro-1-methyl-propyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

To 2- [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 ℃ under a nitrogen atmosphere][1,2,4]Triazol-2-yl]To a solution of butan-2-ol (60mg, 0.22mmol) in dichloromethane (10mL) was added diethylaminosulfur trifluoride (0.14mL, 1.09 mmol). The mixture was stirred at 25 ℃ for 2h, then quenched by the addition of saturated aqueous sodium bicarbonate solution (10 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give any of the named cis- (5S,7S) -2- (1-fluoro-1-methyl-propyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] S as a white solid][1,2,4]Triazole (44.5mg, 73%).¹H NMR(400MHz，CD₃OD)δ7.52–7.15(m，5H)，6.14–6.11(m，0.5H)，5.99–5.97(m，0.5H)，5.58–5.51(m，1H)，3.79–3.65(m,1H)，2.81–2.68(m，1H)，2.14–2.01(m，2H)，1.72–1.66(m，3H)，0.90–0.86(m，3H)。LCMSR_T1.889 min, 277.6[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 min) retention time 1.889 min, ESI + observed [ M + H ] ═ 277.6.

Examples 7 and 8: method 7

Rac- (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R) -1-fluoropropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and rac- (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1S) -1-fluoropropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Cis- (5S,7S) -7-fluoro-2- (1-fluoropropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole was purified by chiral SFC (Chiralcel OX; 150X21.2mm, 5 um; carbon dioxide isocratically eluted with 15% methanol + 0.1% ammonium hydroxide) to give the arbitrarily designated diastereoisomeric rac- (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R) -1-fluoropropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (5mg, 11%) and rac- (5S) as white solids, 7S) -7-fluoro-5-phenyl-2- [ rac- (1S) -1-fluoropropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (3mg, 7%):

the first eluting diastereomer rac- (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R) -1-fluoropropyl]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Analytical data for triazole (arbitrarily designated 5S,7S, 1R configuration): SFC R_T(OX, isocratic elution of carbon dioxide with 10% methanol + 0.1% ammonium hydroxide, 2.5 min method): 0.720 min, 100% ee. LCMS R_T4.65 min, 264.2(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.65 min, ESI + observed [ M + H ] ═ 264.2

Analytical data for the fourth eluted diastereomer (arbitrarily designated 5S,7S, 1S configuration): SFC R_T(OX, isocratic elution of carbon dioxide with 10% methanol + 0.1% ammonium hydroxide, 2.5 min method): 1.338 minutes, 100% ee. LCMSR_T4.67 min, M/z 264.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.67 min, ESI + observed [ M + H ] ═ 264.1

Example 9: method 8

Cis-2- (1, 1-difluoro-2, 2-dimethyl-propyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

Reacting diethylaminosulfur trifluoride(3.68mL, 27.84mmol) and 1- (cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]A mixture of triazol-2-yl) -2, 2-dimethyl-propan-1-one (80mg, 0.28mmol) was stirred at 25 ℃ under nitrogen for 72 h. The mixture was slowly added to saturated aqueous sodium bicarbonate (20mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 50-80%/0.05% aqueous ammonia hydroxide) to give any of the named cis-2- (1, 1-difluoro-2, 2-dimethyl-propyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] s as a white solid][1,2,4]Triazole (30mg, 35%).¹H NMR(400MHz，CD₃OD)δ7.40–7.38(m，3H),7.22–7.20(m，2H)，6.15–6.14(m，0.5H)，6.02–5.99(m，0.5H)，5.62–5.58(m，1H)，3.77–3.69(m，1H)，2.82–2.71(m,1H)，1.07(s，9H)。LCMS R_T2.052 min, M/z 310.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 min) retention time 2.052 min, ESI + observed [ M + H ] ═ 310.1.

Example 10: method 9

Cis- (5S,7S) -7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (E) -cis-7-fluoro-5-phenyl-2- (prop-1-en-1-yl) -6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

To 1- (cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 DEG C][1,2,4]To a solution of triazol-2-yl) propan-1-ol (100mg, 0.38mmol) in acetonitrile (3mL) was added thionyl chloride (228mg, 1.91 mmol). The resulting mixture was stirred at 0 ℃ for 15 minutes and then at 35 ℃ for 1 h. After cooling, the mixture was purified by adding water (1)0mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate/petroleum ether, R)_f0.6) to give (E) -cis-7-fluoro-5-phenyl-2- (prop-1-en-1-yl) -6, 7-dihydro-5H-pyrrolo [1, 2-b) as a light yellow oil][1,2,4]Triazole (30mg, 32%). LCMS R_T0.645 min, M/z 244.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.645 min, ESI + observed [ M + H ] ═ 244.1.

Step 2: cis-7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (E) -cis-7-fluoro-5-phenyl-2- (prop-1-en-1-yl) -6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]A mixture of triazole (30mg, 0.12mmol) and palladium (10% on carbon, 13mg, 0.01mmol) in methanol (5mL) was hydrogenated (15psi) at 25 ℃ for 2h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55%/0.05% aqueous ammonia hydroxide solution) to give the arbitrarily specified cis-7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (16.0mg, 53%).¹H NMR(400MHz，CD₃OD)δ7.39–7.36(m，3H)，7.27–7.25(m，2H)，6.26–6.23(m，0.5H)，6.12–6.09(m，0.5H)，5.60–5.58(m，1H)，3.79–3.70(m，1H)，2.83–2.73(m，3H)，1.79–1.70(m，2H)，0.96–0.92(m，3H)。LCMSR_T1.698 min, M/z 246.2[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 2 minutes) retention time 1.698 minutes, ESI + observed [ M + H ] ═ 246.2.

Example 11: method 10

Cis-2-cyclopropyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Cis-2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (35mg, 0.12mmol), 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (10mg, 0.01mmol), cyclopropylboronic acid (21mg, 0.25mmol) and cesium carbonate (101mg, 0.31mmol) in 1, 4-dioxane (2mL) and water (0.35mL) was heated at 110 ℃ under microwave conditions for 1 h. After cooling, the mixture was diluted with water (15mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 40-70%/0.225% aqueous formic acid) to give the arbitrarily specified cis-2-cyclopropyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (3.1mg, 10%).¹H NMR(400MHz，CD₃OD)δ7.41–7.34(m，3H)，7.22–7.20(m，2H)，6.05–6.02(m，0.5H)，5.90–5.88(m，0.5H)，5.46–5.41(m，1H)，3.73–3.60(m，1H)，2.73–2.62(m，1H)，2.03–1.98(m，1H)，0.99–0.92(m，4H)。LCMS R_T0.827 min, 244.0[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.827 min, ESI + observed [ M + H ] ═ 244.0.

Example 12: method 11

Cis-7-fluoro-5-phenyl-2- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-amine

To cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] under a nitrogen atmosphere][1,2,4]Triazole-2-carboxylic acid (500mg, 2.02mmol)To a mixture in 1, 4-dioxane (30mL) was added anhydrous sodium sulfate (4.0g), triethylamine (0.85mL, 6.07mmol), and diphenylphosphorylazide (1.15mL, 5.06 mmol). The mixture was stirred at 35 ℃ for 18h, and the solution was transferred to a hot solution (95 ℃) of 1, 4-dioxane (30mL) and water (10 mL). The mixture was stirred at 95 ℃ for a further 18h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-mesh, 200-mesh, 0 to 50% ethyl acetate/ethanol (1: 1)/petroleum ether) to give the arbitrarily specified cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-amine (200mg, 45%).¹H NMR(400MHz，CD₃OD)δ7.40–7.35(m，2H)，7.24–7.04(m，3H)，6.00–5.97(m，0.5H)，5.85–5.83(m，0.5H)，5.35–5.30(m，1H)，3.63–3.53(m，1H)，2.63–2.52(m，1H)。LCMS R_T0.617 min, 218.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.617 min, ESI + observed [ M + H ] ═ 218.9.

Example 13: method 12

(5S,7S) -2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]A mixture of methanone (200mg, 0.74mmol) and diethylaminosulfur trifluoride (6.0mL, 44.10mmol) was stirred at 50 ℃ under nitrogen for 72 h. The mixture was slowly added to a stirred saturated aqueous sodium bicarbonate solution (20mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 45-75%/0.05% ammonia) to give any specified rac- (5S,7S) -2- [ cyclopropyl (difluoro) methyl ] as a yellow solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (80mg, 36%).¹H NMR(400MHz，CDCl₃)δ7.42–7.38(m，3H)，7.24–7.22(m，2H)，6.08–5.92(m，1H)，5.48–5.44(m，1H)，3.67–3.57(m，1H)，2.97–2.87(m，1H)，1.81–1.75(m，1H)，0.86–0.82(m，2H)，0.72–0.70(m，2H)。LCMS R_T0.921 min, 293.9[ M + H ]]⁺。

LCMS (5 to 95% aqueous acetonitrile + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.921 min, ESI + observed [ M + H ] ═ 293.9.

Example 14: method 13

(5S,7S) -7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole with (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (100mg, 0.35mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (25mg, 0.04mmol), n-propylboronic acid (37mg, 0.43mmol) and cesium carbonate (347mg, 1.06mmol) in 1, 4-dioxane (2mL) and water (0.35mL) was heated at 80 ℃ under a nitrogen atmosphere for 16 h. After cooling, the mixture was diluted with water (10mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with brine (15mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 43-53%/0.05% aqueous ammonia hydroxide) to give any of the named (5S,7S) -7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (6.2mg, 7%).¹H NMR(400MHz，CD₃OD)δ7.41–7.35(m，3H)，7.22–7.19(m，2H)，6.09–5.92(m，1H)，5.50–5.46(m，1H)，3.75–3.62(m，1H)，2.75–2.64(m，3H),1.79–1.69(m，2H)，0.94(t，J＝7.6Hz，3H)。LCMS R_T1.689 min, M/z 246.2[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 minutes) retention time 1.689 minutes, ESI + observed [ M + H ] ═ 246.2.

Example 15: method 14

(5R,7R) -7-fluoro-5-phenyl-2- (3,3, 3-trifluoropropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5R,7R) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (50mg, 0.18mmol), RuPhos-Pd-G2(14mg, 0.02mmol), potassium 3,3, 3-trifluoropropane-1-trifluoroborate (54mg, 0.27mmol), cesium carbonate (173mg, 0.53mmol) in toluene (3mL) and water (0.3mL) was heated at 100 ℃ under nitrogen for 24h, then concentrated under reduced pressure. The residue was then diluted with water (15mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give any of the named (5R,7R) -7-fluoro-5-phenyl-2- (3,3, 3-trifluoropropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (23.8mg, 44%).¹H NMR(400MHz，CDCl₃)δ7.41–7.37(m，3H)，7.23–7.21(m，2H)，6.04–5.89(m，1H)，5.40–5.36(m，1H)，3.61–3.55(m，1H)，3.06–3.02(m，2H)，2.95–2.85(m，1H)，2.64–2.59(m，2H)。LCMS R_T0.892 min, M/z 299.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.892 min, ESI + found [ M + H ] ═ 299.9.

Example 16: method 15

Trans-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] cyclopropanecarbonitrile

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (100mg, 0.35mmol), (2-cyanocyclopropyl) -potassium trifluoroborate (92mg, 0.53mmol), CataCXium A-Pd-G2(24mg, 0.04mmol), and cesium fluoride (161mg, 1.06mmol) in 1, 4-dioxane (3mL) and water (0.3mL) at 90 ℃ under nitrogenHeating for 15h under the atmosphere. After cooling, the mixture was diluted with water (20mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% aqueous ammonia hydroxide solution) to give any specified trans-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Cyclopropanecarbonitrile (8mg, 8%).¹H NMR(400MHz，CDCl₃)δ7.42–7.39(m，3H)，7.24–7.22(m，2H)，6.00–5.84(m，1H)，5.38–5.34(m，1H)，3.64–3.56(m，1H)，2.92–2.72(m，2H)，2.01–1.94(m，1H)，1.67–1.62(m，2H)。LCMS R_T0.822 min, 269.0[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.822 min, ESI + observed [ M + H ] ═ 269.0.

Example 17: method 16

(5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a cooled (-78 ℃ C.) solution of (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (300mg, 1.06mmol) and N-methoxy-N, 3-dimethyl-oxetane-3-carboxamide (338mg, 2.13mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere was added N-butyllithium (2.5M in hexane, 1.28mL, 3.19 mmol). After addition, the mixture was stirred at-78 ℃ for 1h, then quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% aqueous ammonia hydroxide solution) to give (5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole as a pink solid (190mg, 59%) which was used as such in the next step.

Step 2: (5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]A mixture of triazole (47mg, 0.16mmol) in bis (2-methoxyethyl) aminosulfur trifluoride (3.0mL) was heated at 80 ℃ for 2 h. After cooling, the mixture was diluted with dichloromethane (5mL) followed by ice water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 39-59%/10 mM aqueous ammonium bicarbonate) to give any named (5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl group as a brown oil]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (15.7mg, 31%).¹H NMR(400MHz，CD₃OD)δ7.40–7.36(m，3H)，7.21–7.19(m，2H),6.14–6.11(m，0.5H)，6.00–5.97(m，0.5H)，5.61–5.54(m，1H)，5.01–4.98(m，2H)，4.42–4.36(m，2H)，3.80–3.65(m，1H)，2.83–2.70(m，1H)，1.42(s，3H)。LCMS R_T0.735 min, M/z 324.1[ M + H ═]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.735 min, ESI + observed [ M + H ] ═ 324.1.

Example 18: method 18

(5S,7S) -7-fluoro-5-phenyl-2- (3,3, 3-trifluoropropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (50mg, 0.18mmol), RuPhos-Pd-G2(14mg, 0.02mmol), potassium 3,3, 3-trifluoropropane-1-trifluoroborate (54mg, 0.27mmol), cesium carbonate (173mg, 0.53mmol) in toluene (3mL) and water (0.3mL) was heated at 100 ℃ under nitrogen for 24h, then concentrated under reduced pressure. The residue was then diluted with water (15mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give any of the named (5S,7S) -7-fluoro-5-phenyl-2- (3,3, 3-trifluoropropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (19mg, 34%).¹H NMR(400MHz，CDCl₃)δ7.42–7.36(m，3H)，7.23–7.21(m，2H)，6.04–5.88(m，1H)，5.40–5.36(m，1H)，3.63–3.59(m，1H)，3.06–3.02(m，2H)，2.95–2.85(m，1H)，2.64–2.57(m，2H)。LCMS R_T0.891 min, M/z 299.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.891 min, ESI + found [ M + H ] ═ 299.9.

Example 19: method 19

(5S,7S) -7-fluoro-2- (1-methyl-1H-pyrazol-3-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5 h-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (25mg, 0.09mmol), 1-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1 h-pyrazole (0.01mL, 0.18mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (6mg, 0.01mmol) and potassium carbonate (37mg, 0.27mmol) in 1, 2-dimethoxyethane (1mL) and water (0.2mL) was heated at 120 ℃ for 0.5h under microwave conditions and diluted with water (5 mL). The mixture was extracted with ethyl acetate (3 × 5 mL). Incorporated by referenceThe organic layer was washed with brine (2 × 5mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% aqueous ammonia hydroxide) to give any of the named (5S,7S) -7-fluoro-2- (1-methyl-1H-pyrazol-3-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] S as a pale pink solid][1,2,4]Triazole (6mg, 24%).¹H NMR(400MHz，CD₃OD)δ7.49(d，J＝2.0Hz，1H)，7.46–7.34(m，3H)，7.33–7.20(m，2H)，6.82(d，J＝2.4Hz，1H)，6.25–5.99(m，1H)，5.66–5.59(m，1H)，4.15(s，3H)，3.81–3.71(m，1H)，2.85–2.74(m，1H)。LCMS R_T1.621 min, 284.2[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 min) retention time 1.621 min, ESI + observed [ M + H ] ═ 284.2.

Example 20: method 20

(5S,7S) -2- [ (2, 2-Difluorocyclopropyl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (5S,7S) -2-allyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (150mg, 0.53mmol), allylboronic acid pinacol ester (179mg, 1.06mmol), RuPhos-Pd-G2(41mg, 0.05mmol), cesium carbonate (520mg, 1.60mmol) in 1, 4-dioxane (5mL) and water (1mL) was heated at 100 ℃ under nitrogen atmosphere for 12h, then concentrated under reduced pressure. The residue was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (35% ethyl acetate/petroleum ether R)_f═ 0.4) purification to give (5S,7S) -2-allyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo as a colorless oil[1,2-b][1,2,4]Triazole (90mg, 70%). LCMS R_T0.733 min, M/z 244.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.733 min, ESI + observed [ M + H ] ═ 244.1.

Step 2: (5S,7S) -2- [ (2, 2-Difluorocyclopropyl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To (5S,7S) -2-allyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]To a solution of triazole (50mg, 0.21mmol) in toluene (1mL) were added benzyltriethylammonium chloride (6mg, 0.02mmol) and [ chloro (difluoro) methyl]Trimethylsilane (98mg, 0.62 mmol). The mixture was heated at 110 ℃ under microwave conditions for 4h and diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% aqueous ammonia hydroxide solution) to give the arbitrarily specified (5S,7S) -2- [ (2, 2-difluorocyclopropyl) methyl group as a white solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (10.7mg, 17%).¹H NMR(400MHz，CDCl₃)δ7.41–7.36(m，3H)，7.24–7.22(m，2H)，6.05–5.89(m，1H)，5.41–5.37(m，1H)，3.63–3.55(m，1H)，3.06–3.03(m，1H)，2.85–2.81(m，2H)，2.01–2.00(m，1H)，1.50–1.46(m，1H)，1.16–1.11(m，1H)。LCMS R_T1.775 min, M/z 294.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia, 3.0 min) retention time: 1.775 min, ESI + found [ M + H ] ═ 294.1.

Example 21: method 21

Racemic ethyl- (1R,2R) -2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] cyclopropanecarboxylate

To a solution of ethyl diazoacetate (0.85g, 7.42mmol) in toluene (20mL) was added (5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (170mg, 0.74 mmol). The reaction mixture was heated at 110 ℃ for 12h and concentrated under reduced pressure. The residue was first passed through preparative TLC (40% ethyl acetate/petroleum ether, R)_f＝0.3&0.4) purification followed by RP-HPLC (acetonitrile 5-55%/0.05% aqueous ammonia hydroxide solution) to give any specified rac- (1R,2R) -2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a colorless oil][1,2,4]Triazol-2-yl]Cyclopropanecarboxylic acid ethyl ester (120mg, 50%).¹H NMR(400MHz，CDCl₃)δ7.39–7.36(m，3H)，7.23–7.20(m，2H)，5.99–5.96(m，0.5H)，5.85–5.82(m，0.5H)，5.35–5.31(m，1H)，4.17–4.11(m，2H)，3.58–3.48(m，1H)，2.90–2.80(m，1H)，2.65–2.63(m，1H)，2.22–2.15(m，1H)，1.58–1.55(m，2H)，1.27–1.23(m，3H)。LCMS R_T0.890 min, 316.0[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.890 min, ESI + observed [ M + H ] ═ 316.0.

Any given rac- (1R,2S) -2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a colorless oil][1,2,4]Triazol-2-yl]Cyclopropanecarboxylic acid ethyl ester (30mg, 13%).¹H NMR(400MHz，CD₃OD)δ7.46–7.32(m，3H)，7.25–7.17(m，2H)，6.10–6.04(m，0.5H)，5.96–5.90(m，0.5H)，5.54–5.47(m，1H)，4.01–3.93(m，1H)，3.93–3.87(m，1H)，3.75–3.59(m，1H)，2.78–2.62(m，1H)，2.61–2.53(m，1H)，2.18–2.10(m，1H)，1.80–1.72(m，1H)，1.50–1.41(m，1H)，1.13–1.04(m，3H)。LCMS R_T0.730 min, 316.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.730 min, ESI + observed [ M + H ] ═ 316.1.

Example 22: method 22

3- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propionitrile

Step 1: rac- (5S,7S) - (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methanol

To a solution of rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carboxylic acid ethyl ester (520mg, 1.89mmol, 1.0 equiv.) in ethanol (10mL) cooled to 0 ℃ was added lithium borohydride (2M in tetrahydrofuran, 5.66mL, 11.33mmol, 6.0 equiv.). The ice bath was removed and the mixture was stirred at room temperature for 6 h. After this time, the reaction mixture was poured into 5% aqueous citric acid (100 mL). The mixture was extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give rac- (5S,7S) - (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methanol as a white solid, which was used without further purification (428mg, 97% yield).

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 0.88 min, ESI + observed [ M + H ] ═ 234.

Step 2: rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carbaldehyde

To rac- (5S,7S) - (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]To a solution of triazol-2-yl) methanol (420mg, 1.8mmol, 1.0 equiv.) in dichloromethane (8mL) was added Dess-Martin periodinane (866mg, 1.98mmol, 1.1 equiv.). The mixture was stirred at room temperature for 2 h. After this time, it was diluted with dichloromethane (75mL)Release, 100mL of 1: 110% NaHCO₃Aqueous solution/20% Na₂S₂O₃Quenched and stirred at room temperature for 30 minutes. The layers were separated and the dichloromethane layer was washed with brine, dried over sodium sulfate and concentrated to give rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a yellow residue][1,2,4]Triazole-2-carbaldehyde, which was used in the next step without further purification (410mg, 98% yield).

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 1.04 min, ESI + observed [ M + H ] ═ 232.

And step 3: (E) -rac- (5S,7S) -3- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propan-2-enenitrile and (Z) -rac- (5S,7S) -3- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propan-2-enenitrile

To a solution of diethyl cyanomethylphosphonate (0.324mL, 354mg, 2.0mmol, 1.1 equiv.) in tetrahydrofuran (10mL) was added potassium tert-butoxide (1M in tetrahydrofuran, 1.9mL, 1.9mmol, 1.05 equiv.). The resulting mixture was stirred at room temperature for 1H, and then rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] in tetrahydrofuran (10mL) was added thereto][1,2,4]Triazole-2-carbaldehyde (420mg, 1.82mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 16 h. After this time, the reaction was quenched with 5% aqueous citric acid (75mL) and extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with saturated NaHCO₃Washed with water and brine, dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography (silica gel, 100 mesh, 200 mesh, 0 to 100% isopropyl acetate/heptane) to give (E) -rac- (5S,7S) -3- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) prop-2-enenitrile (155mg, 34% yield) and (Z) -rac- (5S,7S) -3- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) prop-2-enenitrile (90mg, 20% yield).

(E) Isomers: LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 1.16 min, ESI + observed [ M + H ] ═ 255.

(Z) isomer: LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 1.11 min, ESI + observed [ M + H ] ═ 255.

And 4, step 4: 3- ((5R,7R) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propionitrile and 3- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propionitrile

To a solution of (Z) -rac- (5S,7S) -3- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) prop-2-enenitrile in tetrahydrofuran (5mL) and ethanol (5mL) was added sodium borohydride (80mg, 2.1mmol, 6.0 equiv.). The mixture was stirred at 50 ℃ for 3 h. After this time, the mixture was filtered through a plug of silica gel, eluted with isopropyl acetate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate/heptane) to give rac- (5S,7S) -3- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propionitrile as a white solid (60mg, 66% yield). The racemic material was further separated by chiral SFC to give any of the named:

3- ((5R,7R) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) propionitrile

(Peak 1, SFC assay retention time 0.73 min, Whelk-O1(S, S), isocratic 15% MeOH + 0.1% NH)₄OH, 2.5 min method) (19.1mg, 21%) as a white solid.¹H NMR(400MHz，DMSO-d6)δ7.45–7.30(m，3H)，7.26–7.15(m，2H)，6.14(ddd，J＝57.0，7.1，1.7Hz，1H)，5.66–5.52(m，1H)，3.77–3.59(m，1H)，3.06–2.95(m，2H)，2.94–2.81(m，2H)，2.70–2.56(m，1H)。LC-MS R_T3.78 min, M/z 257.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.78 min, ESI + observed [ M + H ] ═ 257.1.

(Peak 2, SFC assay retention time 0.86 min, Whelk-O1(S, S), isocratic 15% MeOH + 0.1% NH)₄OH, 2.5 min method) (21.0mg, 23%) as a white solid.¹H NMR(400MHz，DMSO-d6)δ7.47–7.29(m，3H)，7.26–7.13(m，2H)，6.14(ddd，J＝57.0，7.1，1.7Hz，1H)，5.59(ddd，J＝8.3，7.1，2.8Hz，1H)，3.79–3.57(m，1H)，3.06–2.94(m，2H)，2.93–2.81(m，2H)，2.73–2.54(m，1H)。LC-MS R_T3.78 min, M/z 257.1(M + H)⁺。

SFC conditions (preparative): column: whelk O-1(S, S) 150X21.2mm I.D., 5um mobile phase: a: CO 2B: methanol, isocratic 20% methanol for 25 minutes, flow rate: 80 mL/min, column temperature 40 ℃.

Example 23: method 23

(5S,7S) -2- [ difluoro- (rac- (1R,2R) -2-fluorocyclopropyl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Coupling (trans-2-fluorocyclopropyl) - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazol-2-yl]A mixture of methanone (44mg, 0.15mmol) in diethylaminosulfur trifluoride (2.0g, 12.41mmol) was heated at 50 ℃ for 24h and then slowly added to saturated aqueous sodium bicarbonate solution (20 mL). The resulting mixture was extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give the crude product, which was purified by preparative TLC (40% ethyl acetate/petroleum ether, R)_f0.5) to give arbitrarily designated (5S,7S) -2- [ difluoro- (rac) as a white solid- (1R,2R) -2-fluorocyclopropyl) methyl]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (7.2mg, 15%).¹H NMR(400MHz，CDCl₃)δ7.44–7.39(m，3H)，7.26–7.24(m，2H)，6.10–6.08(m，1H)，5.50–5.45(m，1H)，4.92–4.75(m，1H)，3.69–3.58(m，1H)，3.00–2.90(m，1H)，2.31–2.25(m，1H)，1.43–1.36(m，1H)，1.24–1.19(m，1H)。LCMS R_T1.931 min, 312.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.05% ammonium hydroxide for 3 min) retention time 1.931 min, ESI + observed [ M + H ] ═ 312.1.

Example 24: method 24

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R,2R) -2- (methoxymethyl) cyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (trans-2- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) cyclopropyl) methanol

Racemic- (1R,2R) -2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 deg.C][1,2,4]Triazol-2-yl]To a cooled solution of ethyl cyclopropanecarboxylate (60mg, 0.19mmol) in tetrahydrofuran (2mL) was added lithium aluminum hydride (14mg, 0.38 mmol). After addition, the mixture was stirred at 0 ℃ for 1h and quenched by the addition of water (0.05 mL). The resulting mixture was diluted with ethyl acetate (10 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate/petroleum ether, R)_f0.4) to give any given rac- (1R,2R) -2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a white solid][1,2,4]Triazol-2-yl]Cyclopropylmethanol (45mg, 87%).¹H NMR(400MHz，CD₃OD)δ7.45–7.33(m，3H)，7.27–7.20(m，2H)，6.07–6.05(m，0.5H)，5.93–5.90(m，0.5H)，5.50–5.43(m，1H)，3.76–3.55(m，2H)，3.52–3.44(m，1H)，2.78–2.63(m，1H)，1.99–1.94(m，1H)，1.70–1.58(m，1H),1.18–1.12(m，1H)，1.02–0.94(m，1H)。LCMS R_T0.654 min, M/z 274.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.654 min, ESI + observed [ M + H ] ═ 274.1.

Step 2: (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R,2R) -2- (methoxymethyl) cyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Racemic- (1R,2R) -2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 deg.C][1,2,4]Triazol-2-yl]To a cooled solution of cyclopropylmethanol (45mg, 0.16mmol) in tetrahydrofuran (2mL) was added sodium hydride (60%, 13mg, 0.33 mmol). The mixture was stirred at 0 ℃ for 2min, then methyl iodide (47mg, 0.33mmol) was added. After addition, the mixture was stirred at 0 ℃ for 1h and quenched by addition of water (5 mL). The resulting mixture was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 24-54%/0.05% aqueous ammonia hydroxide solution) to give any of the named (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R,2R) -2- (methoxymethyl) cyclopropyl-2- [ as a white solid]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (9.9mg, 21%).¹H NMR(400MHz，CD₃OD)δ7.40–7.29(m，3H)，7.20–7.17(m，2H)，6.03–6.01(m，0.5H)，5.89–5.86(m，0.5H)，5.45–5.39(m，1H)，3.71–3.56(m，1H)，3.47–3.41(m，1H)，3.30(s，3H)，3.30–3.24(m，1H)，2.72–2.59(m，1H)，1.96–1.91(m，1H)，1.66–1.54(m，1H)，1.18–1.08(m，1H)，0.98–0.90(m，1H)。LCMS R_T0.724 min, M/z 288.2[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.724 min, ESI + observed [ M + H ] ═ 288.2.

Example 25: method 25

(5S,7S) -7-fluoro-2- (4-methyl-1H-pyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (100mg, 0.35mmol), cuprous iodide (14mg, 0.07mmol), (1S,2S) -N¹,N²A mixture of-dimethylcyclohexane-1, 2-diamine (50mg, 0.35mmol), cesium carbonate (346mg, 1.06mmol) and 4-methylpyrazole (291mg, 3.54mmol) in 1, 4-dioxane (2mL) was heated under microwave conditions in a sealed tube at 140 ℃ for 3 minutes. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-50%/0.05% aqueous ammonia hydroxide) to give any of the named (5S,7S) -7-fluoro-2- (4-methylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] S as a yellow solid][1,2,4]Triazole (8mg, 8%).¹H NMR(400MHz，CD₃OD)δ8.05(s，1H)，7.57(s，1H)，7.44–7.29(m，5H)，6.18–6.02(m，1H)，5.62–5.56(m，1H)，3.78–3.85(m，1H)，2.80–2.69(m，1H)，2.14(s，3H)。LCMS R_T0.710 min, M/z 283.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.710 min, ESI + observed [ M + H ] ═ 283.9.

Example 26: method 26

(S) -5- (2-fluorophenyl) -2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (S, E) -5- (2-fluorophenyl) -2- (prop-1-en-1-yl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (S) -2-bromo-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (20mg, 0.07mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (5mg, 0.01mmol), 4,5, 5-tetramethyl-2- [ (1E) -prop-1-en-1-yl]A mixture of-1, 3, 2-dioxaborolan (24mg, 0.14mmol) and cesium carbonate (70mg, 0.21mmol) in 1, 4-dioxane (2mL) and water (0.4mL) was heated at 100 ℃ under nitrogen atmosphere for 16h and concentrated under reduced pressure. The aqueous residue was diluted with water (15mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude (S) -5- (2-fluorophenyl) -2- [ (E) -prop-1-enyl) -as a dark oil]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (40mg, crude, 100%). LCMS R_T0.603 min, 244.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.603 min, ESI + observed [ M + H ] ═ 244.1.

Step 2: (S) -5- (2-fluorophenyl) -2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (S) -5- (2-fluorophenyl) -2- [ (E) -prop-1-enyl]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]A mixture of triazole (40mg, 0.16mmol) and palladium (10% on carbon, 175mg, 0.16mmol) in methanol (5mL) was hydrogenated (15psi) at 30 ℃ for 16h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide solution) to give the arbitrarily designated (S) -5- (2-fluorophenyl) -2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (11.6mg, 41%).¹H NMR(400MHz，CD₃OD)δ7.42–7.36(m，1H)，7.21–7.07(m，3H)，5.69–5.66(m，1H)，3.29–3.22(m，1H)，3.08–3.00(m，2H)，2.67–2.58(m，3H)，1.78–1.68(m，2H)，0.94(t，J＝7.2Hz，3H)。LCMS R_T1.588 min, 246.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.05% ammonia hydroxide for 3 minutes) retention time 1.588 minutes with ESI + observed [ M + H ] ═ 246.1.

Examples 27 and 32: method 27

(5S,7S) -7-fluoro-5-phenyl-2- [ (S) -1-fluoro-1-methyl-propyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -7-fluoro-5-phenyl-2- [ (R) -1-fluoro-1-methyl-propyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: 2- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) butan-2-ol

To 1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 ℃ under a nitrogen atmosphere][1,2,4]Triazol-2-yl]To a solution of propan-1-one (89mg, 0.34mmol) in tetrahydrofuran (5mL) was added methyl magnesium bromide (3.0M in diethyl ether, 0.46mL, 1.37mmol) dropwise. After addition, the resulting mixture was stirred at 0 ℃ for 1h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were concentrated under reduced pressure and the residue was passed through preparative TLC (50% ethyl acetate/petroleum ether, R)_f0.6) to give 2- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a yellow oil][1,2,4]Triazol-2-yl) butan-2-ol (60mg, 64%). LCMS R_T0.579 min, M/z 276.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.579 min, ESI + observed [ M + H ] ═ 276.1.

Step 2 (5S,7S) -7-fluoro-5-phenyl-2- [ (S) -1-fluoro-1-methyl-propyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -7-fluoro-5-phenyl-2- [ (R) -1-fluoro-1-methyl-propyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To 2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 ℃ under a nitrogen atmosphere][1,2,4]Triazol-2-yl]To a solution of butan-2-ol (60mg, 0.22mmol) in dichloromethane (10mL) was added diethylaminosulfur trifluoride (0.14mL, 1.09 mmol). The mixture was stirred at 25 ℃ for 2h, then quenched by the addition of saturated aqueous sodium bicarbonate solution (10 mL). The resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were concentrated under reduced pressure and the residue was passed through preparative TLC (50% ethyl acetate/petroleum ether, R)_f0.3) to give crude (5S,7S) -7-fluoro-2- (1-fluoro-1-methyl-propyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a white solid][1,2,4]Triazole (80mg, 128%). The racemic material (80mg) was further purified by chiral SFC to give any of the named:

(5S,7S) -7-fluoro-5-phenyl-2- [ (S) -1-fluoro-1-methyl-propyl ] as white solid]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (peak 1, retention time 2.008 min) (26mg, 32%).¹H NMR(400MHz，CD₃OD)δ7.42–7.35(m，3H)，7.23–7.22(m，2H)，6.13–5.97(m，1H)，5.57–5.52(m，1H)，3.79–3.69(m，1H)，2.80–2.69(m，1H)，2.13–2.02(m，2H)，1.69(d，J＝22.0Hz，3H)，0.88(t，J＝7.6Hz，3H)。LCMS R_T0.732 min, 278.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.732 min, ESI + observed [ M + H ] ═ 278.0.

(5S,7S) -7-fluoro-5-phenyl-2- [ (R) -1-fluoro-1-methyl-propyl ] as white solid]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (peak 2, retention time 2.589 min) (24mg, 29%).¹H NMR(400MHz，CD₃OD)δ7.43–7.35(m，3H)，7.23–7.21(m，2H)，6.14–5.97(m，1H)，5.57–5.52(m，1H)，3.79–3.65(m，1H)，2.80–2.69(m，1H)，2.13–2.02(m，2H)，1.69(d，J＝21.6Hz，3H)，0.88(t，J＝7.6Hz，3H)。LCMS R_T0.857 min, M/z 278.0[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.857 min, ESI + observed [ M + H ] ═ 278.0.

SFC conditions: column: ChiralPak IC-3150 × 4.6mm i.d., 3um gradient: CO2₂5% to 40% IPA (0.05% DEA), flow rate: 2.5 mL/min. Column temperature: 40 ℃ example 28: method 28

(5S,7S) -2- (2, 2-Difluorocyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (150mg, 0.53mmol), potassium vinyltrifluoroborate (142mg, 1.06mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (78mg, 0.11mmol) and cesium carbonate (520mg, 1.60mmol) in 1, 4-dioxane (30mL) and water (3mL) was heated at 100 ℃ under nitrogen atmosphere for 16 h. After cooling, the mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate/petroleum ether) to give (5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (100mg, 82%). LCMS R_T0.606 min, M/z 230.2[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.606 min, ESI + observed [ M + H ] ═ 230.2.

Step 2: (5S,7S) -2- (2, 2-Difluorocyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (50mg, 0.22mmol) and [ chloro (difluoro) methyl group]A mixture of trimethylsilane (10mg, 0.65mmol) and tetrabutylammonium chloride (6mg, 0.02mmol) in toluene (1mL) was heated at 110 ℃ under microwave conditions for 4h, then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonium bicarbonate) to give any of the named (5S,7S) -2- (2, 2-difluorocyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a light yellow solid][1,2,4]Triazole (28.3mg, 46%).¹H NMR(400MHz，CDCl₃)δ7.42–7.38(m，3H)，7.23–7.21(m，2H)，6.06–5.89(m，1H)，5.42–5.38(m，1H)，3.62–3.55(m，1H)，2.93–2.85(m，2H)，2.18–2.10(m，1H)，1.88–1.84(m，1H)。LCMS R_T0.826 min, 279.9[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.826 min, ESI + observed [ M + H ] ═ 279.9.

Example 29: method 29

(5S,7S) -2- (3, 3-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (5S,7S) -2- [ (E) -3, 3-diethoxyprop-1-enyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrroleAnd [1,2-b ]][1,2,4]Triazole (100mg, 0.35mmol) and 2- [ (E) -3, 3-diethoxyprop-1-enyl]A mixture of-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (182mg, 0.71mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (52mg, 0.07mmol) and cesium carbonate (347mg, 1.06mmol) in 1, 4-dioxane (2mL) and water (0.2mL) was heated at 90 ℃ under nitrogen atmosphere for 16 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give crude (5S,7S) -2- [ (E) -3, 3-diethoxyprop-1-enyl) as a yellow oil]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (100mg, 85%). The crude product was used in the next step without further purification. LCMS R_T0.694 min, 332.2[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.694 min, ESI + observed [ M + H ] ═ 332.2.

Step 2: (E) -3- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] prop-2-enal

Reacting (5S,7S) -2- [ (E) -3, 3-diethoxyprop-1-enyl]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]A mixture of triazole (100mg, 0.30mmol) and hydrochloric acid (12M, 0.25mL, 3.02mmol) in acetonitrile (5mL) was stirred at 25 ℃ for 1h, then adjusted to pH 8 by the addition of aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were concentrated under reduced pressure to give (E) -3- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a brown solid][1,2,4]Triazol-2-yl]Prop-2-enal (70mg, 90%). LCMS R_T0.595 min, 258.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.595 min, ESI + observed [ M + H ] ═ 258.1.

And step 3: (5S,7S) -2- [ (E) -3, 3-Difluoroprop-1-enyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To (E) -3- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 deg.C][1,2,4]Triazol-2-yl]To a solution of prop-2-enal (60mg, 0.23mmol) in dichloromethane (3mL) was slowly added diethylaminosulfur trifluoride (150mg, 0.93 mmol). The reaction mixture was stirred at 0 ℃ for 2h, then quenched by the slow addition of saturated aqueous sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate/petroleum ether, R)_f0.3) to give (5S,7S) -2- [ (E) -3, 3-difluoropropan-1-enyl) as a white solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (50mg, 77%). LCMS R_T0.666 min, M/z 280.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.666 min, ESI + observed [ M + H ] ═ 280.1.

And 4, step 4: (5S,7S) -2- (3, 3-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2- [ (E) -3, 3-difluoroprop-1-enyl]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]A mixture of triazole (50mg, 0.18mmol) and palladium (10% on carbon, 25mg) in methanol (5mL) was hydrogenated (15psi) at 25 ℃ for 1h, then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% aqueous ammonia hydroxide solution) to give the arbitrarily designated (5S,7S) -2- (3, 3-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (20mg, 38%).¹H NMR(400MHz，CD₃OD)δ7.43–7.32(m，3H)，7.23–7.22(m，2H)，6.11–5.83(m，2H)，5.50–5.48(m，1H)，3.74–3.64(m，1H)，2.92–2.88(m，2H)，2.71–2.69(m，1H)，2.28–2.23(m，2H)。LCMS R_T0.843 min, 281.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.587 min, ESI + observed [ M + H ] ═ 281.9.

Example 30: method 30

(5S,7S) -2- (2, 2-dimethylcyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: (2, 2-dimethylcyclopropyl) -trifluoroborate potassium salt

To a solution of 2- (2, 2-dimethylcyclopropyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (200mg, 1.02mmol) in methanol (4mL) was added a solution of potassium bifluoride (558mg, 7.14mmol) in water (0.8 mL). The mixture was stirred at 25 ℃ for 16h and then concentrated under reduced pressure. The residue was extracted with acetonitrile (3 × 10 mL). The combined organic layers were concentrated and the residue triturated with petroleum ether (10 mL). The resulting solid was collected by filtration to give crude potassium (2, 2-dimethylcyclopropyl) -trifluoroborate (60mg, 33%) as a white solid.¹H NMR(400MHz，DMSO-d₆)δ0.95(s，3H)，0.93(s，3H)，-0.10–-0.12(m，2H)，-0.85–-0.90(m，1H)。

Step 2: (5S,7S) -2- (2, 2-dimethylcyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (50mg, 0.18mmol), RuPhos-Pd-G2(14mg, 0.02mmol), (2, 2-dimethylcyclopropyl) -potassium trifluoroborate (47mg, 0.27mmol), cesium carbonate (173mg,0.53mmol) in toluene (2mL) and water (0.2mL) was heated at 100 ℃ under nitrogen for 24h and concentrated under reduced pressure. The residue was diluted with water (15mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 45-75%/0.05% aqueous ammonia hydroxide) to give any of the named (5S,7S) -2- (2, 2-dimethylcyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (26.2mg, 54%).¹H NMR(400MHz，CDCl₃)δ7.38–7.35(m，3H)，7.20–7.18(m，2H)，6.01–5.85(m，1H)，5.37–5.35(m，1H)，3.58–3.51(m，1H)，2.85–2.79(m，1H)，1.97–1.94(m，1H)，1.20(s，3H)，1.18–1.15(m，1H)，1.03(d，J＝8.4Hz，3H)，0.90–0.88(m，1H)。LCMS R_T0.889 min, M/z 272.0[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.889 min, ESI + observed [ M + H ] ═ 272.0

Example 31: method 31

(5S,7S) -7-fluoro-5-phenyl-2- (1H-pyrazol-1-yl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (100mg, 0.35mmol), cuprous iodide (13mg, 0.07mmol), (1S,2S) -N¹,N²A mixture of-dimethylcyclohexane-1, 2-diamine (50mg, 0.35mmol), cesium carbonate (346mg, 1.06mmol) and pyrazole (241mg, 3.54mmol) in 1, 4-dioxane (2mL) was heated under microwave conditions in a sealed tube at 140 ℃ for 3 minutes and then concentrated under reduced pressure. The residue was first purified by RP-HPLC (acetonitrile 31-51%/0.05% aqueous ammonia hydroxide solution) and then by SFC to give the arbitrarily designated (5S,7S) -7-fluoro-5-phenyl-2-pyrazol-1-yl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (retention time 4.814 min) (15mg, 16%).¹H NMR(400MHz，CD₃OD)δ8.30(d，J＝2.4Hz，1H)，7.75(s，1H)，7.44–7.30(m，5H)，6.55–6.54(m，1H)，6.20–6.03(m，1H)，5.62–5.58(m，1H)，3.80–3.66(m，1H)，2.82–2.70(m，1H)。LCMS R_T0.809 min, 269.9[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.809 min, ESI + observed [ M + H ] ═ 269.9.

SFC conditions: column: OD (250mm x30mm, 5um), mobile phase: a: CO2₂B: ethanol (0.1% NH)₃H₂O) gradient: 5% to 40% B and hold 40% for 2.5 minutes over 5 minutes, then 5% B for 2.5 minutes. Flow rate: column temperature of 60 mL/min 35 ℃.

Example 33: method 32

(5S,7S) -7-fluoro-5-phenyl-2- (2- (trifluoromethyl) cyclopropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (200mg, 0.71mmol), dibutoxy- [2- (trifluoromethyl) cyclopropyl]Borane (226mg, 0.85mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl ]]A mixture of palladium (ii) (59mg, 0.07mmol) and cesium carbonate (693mg, 2.13mmol) in 1, 4-dioxane (3mL) and water (0.5mL) was heated at 100 ℃ under microwave conditions for 1.5 h. The reaction was diluted with water (5mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (2 × 15mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was first passed through preparative TLC (35% ethyl acetate/petroleum ether, R)_f0.7) followed by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide) to give arbitrarily specified (5S,7S) -7-fluoro-5-phenyl-2- [2- (trifluoromethyl) cyclopropyl ] as a white solid]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (5.6mg, 3%).¹H NMR(400MHz，CD₃OD)δ7.42–7.37(m，3H)，7.24–7.22(m，2H)，6.08–6.05(m，0.5H)，5.93–5.91(m，0.5H)，5.49–5.46(m，1H)，3.70–3.62(m，1H)，2.76–2.65(m，1H)，2.47–2.43(m，1H)，2.23–2.21(m，1H)，1.44–1.39(m，2H)。LCMS R_T0.804 min, 312.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time: at 0.804 min, ESI + found [ M + H ] — 312.1.

Examples 34 and 35: method 33

(S) -cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol and (R) -cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

Cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 DEG C][1,2,4]Triazol-2-yl]To a solution of methanone (70mg, 0.26mmol) in methanol (4mL) was added sodium borohydride (49mg, 1.29 mmol). The mixture was stirred at 0 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by preparative TLC (petroleum ether: ethyl acetate ═ 1:1) to give any specified cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Methanol (58mg, 82%). LCMS R_T0.588 min, 274.2[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.588 min, ESI + observed [ M + H ] ═ 274.2.

The racemic material (58mg, 0.21mmol) was further separated by chiral SFC to give any of the named:

(S) -cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Methanol (peak 1, retention time 3.277 min) (15.1mg, 26%).¹H NMR(400MHz，CDCl₃) δ 7.42-7.36 (m, 3H), 7.24-7.22 (m, 2H), 6.06-5.91 (m, 1H), 5.44-5.39 (m, 1H), 4.27-4.24 (m, 1H), 3.63-3.55 (m, 1H), 2.94-2.83 (m, 1H), 2.54-2.52 (m, 1H), 1.43-1.38 (m, 1H), 0.64-0.58 (m, 2H), 0.50-0.48 (m, 2H). LCMS RT 1.345 min, M/z 274.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 3 minutes) retention time 1.345 minutes, ESI + observed [ M + H ] ═ 274.1.

(R) -cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Methanol (peak 2, retention time 4.193 min) (31.5mg, 54%).¹H NMR(400MHz，CDCl₃)δ7.42–7.37(m，3H)，7.24–7.22(m，2H)，6.07–5.91(m，1H)，5.43–5.40(m，1H)，4.24–4.22(m，1H)，3.65–3.55(m，1H)，2.93–2.83(m，1H),2.60–2.59(m，1H)，1.41–1.36(m，1H)，0.64–0.47(m，4H)。LCMS R_T1.325 min, M/z 274.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 3 minutes) retention time 1.325 minutes, ESI + observed [ M + H ] ═ 274.1.

SFC conditions: column: lux Cellulose-2150 × 4.6mm i.d., 3um, mobile phase: a: CO2₂B: ethanol (0.05% DEA) gradient: 5% to 40% B and hold 40% for 2.5 minutes in 5 minutes, then 5% B for 2.5 minutes flow rate: 2.5mL/min column temperature 40 ℃.

Example 36: method 34

(5S,7S) -2-Ethyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a 2 dram (dram) vial equipped with a pressure reducing lid was charged (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (50mg, 0.18mmol), potassium ethyltrifluoroborate (5 equiv., 0.89mmol), palladium (II) acetate (0.2 equiv., 0.04mmol), butyl bis-1Adamantylphosphine (0.3 eq, 0.05mmol) and cesium carbonate (4 eq, 0.71mmol) and the vial was purged with nitrogen for 2 minutes. Toluene (5mL) and water (0.5mL) were added and the reaction was stirred at 110 ℃ for 72 h. Reaction mixture is passed through

The plug was filtered and concentrated in vacuo. The crude mixture was diluted with ethyl acetate (15mL) and washed with water (2 × 15mL), brine (15mL) and dried using Sep-Pak (sodium sulfate). The organic layer was evaporated to dryness and 20-60% ACN (0.1% NH) by preparative HPLC₄Aqueous OH solution for aqueous modifier) to obtain (5S,7S) -2-ethyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (9.3mg, 23%).

1H NMR(400MHz，DMSO-d6)δ7.52–7.23(m，3H)，7.31–7.05(m，2H)，6.09(ddd，J＝57.2，7.1，1.7Hz，1H)，5.65–5.41(m，1H)，3.82–3.48(m，1H)，2.70–2.53(m，3H)，1.20(t，J＝7.6Hz，3H)。LCMS R_T4.07 min, M/z 232.1[ M + H ]]⁺。

LCMS (2 to 98% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.07 min, ESI + found 232.1[ M + H%]⁺。

Example 37: method 34

(5S,7S) -7-fluoro-2- (Isopropoxymethyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (4.5mg, 9% yield)

1H NMR(400MHz，DMSO-d6)δ7.44–7.32(m，3H)，7.24–7.17(m，2H)，6.14(ddd，J＝57.0，7.1，1.7Hz，1H)，5.63–5.54(m，1H)，4.42(s，2H)，3.76–3.58(m，2H)，2.70–2.56(m，1H)，1.09(d，J＝6.1Hz，6H)。LC-MS R_T4.43 min, M/z 276.1(M + H)⁺。

LCMS (2 to 98% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.43 min, ESI + found 276.1[ M + H [ ]]⁺。

Example 38: method 34

(5S,7S) -2- (2-ethoxyethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (2.1mg, 4%)

LCMS (2 to 98% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.24 min, ESI + found 276.1[ M + H [ ]]⁺。

Example 39: method 35

(5S,7S) -7-fluoro-2- (4-isopropylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

A microwave vial equipped with a stir bar was charged with (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (50mg, 0.18mmol), 4-isopropyl-1H-pyrazole hydrochloride (10 equiv., 1.77mmol), cesium carbonate (5 equiv., 0.89mmol), cuprous iodide (1.2 equiv., 0.21mmol), trans-N, N' -dimethylcyclohexane-1, 2-diamine (8 equiv., 1.42mmol), and 1, 4-dioxane (1.7mL), degassed with nitrogen and added to the reaction. The microwave vial was sealed and heated to 140 ℃ with stirring for 20 minutes. The mixture was then diluted with ethyl acetate (5mL), washed with water (2 × 5mL), and the organic layer was dried using Sep-Pak (sodium sulfate) and evaporated to dryness. The crude mixture was purified by preparative HPLC 30-70% ACN (0.1% aqueous formic acid for aqueous modifier) to give (5S,7S) -7-fluoro-2- (4-isopropylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (3.8mg, 6%).

¹H NMR(400MHz，DMSO-d6)δ8.11(s，1H)，7.69(s，1H)，7.47–7.35(m，3H)，7.32–7.23(m，2H)，6.23(ddd，J＝56.8，7.2，1.8Hz，1H)，5.66(td，J＝8.0，2.9Hz，1H)，3.87–3.58(m，1H)，2.85(hept，J＝13.9，6.9Hz，1H)，2.72–2.56(m，1H)，1.20(d，J＝6.8Hz，6H)。LCMSR_T5.44 min, m/z 312.1[M+H]⁺。

LCMS (2 to 98% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.44 min, ESI + found 312.1[ M + H [ ]]⁺。

Example 40: method 36

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-4-carbaldehyde

A microwave vial equipped with a stir bar was charged with (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (50mg, 0.18mmol), 1H-pyrazole-4-carbaldehyde (10 equiv., 1.77mmol), cesium carbonate (3 equiv., 0.53mmol), cuprous iodide (1.2 equiv., 0.21mmol), trans-n, n' -dimethylcyclohexane-1, 2-diamine (8 equiv., 1.42mmol), and 1, 4-dioxane (1.7mL), degassed with nitrogen and added to the reaction. The microwave vial was sealed and heated to 140 ℃ for 20 minutes with stirring. The mixture was diluted with ethyl acetate (5mL) and washed with water (2 × 5 mL). The organic layer was dried using Sep-Pak (sodium sulfate) and evaporated to dryness. The crude mixture was purified by preparative HPLC 5-50% ACN (0.1% aqueous formic acid for aqueous modifier) to give 1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-4-carbaldehyde (15mg, 28%).

¹H NMR(400MHz，DMSO-d6)δ9.93(s，1H)，9.14(d，J＝0.6Hz，1H)，8.27(d，J＝0.6Hz，1H)，7.56–7.36(m，3H)，7.35–7.20(m，2H)，6.28(ddd，J＝56.6，7.2，1.9Hz，1H)，5.72(td，J＝8.0，3.1Hz，1H)，3.86–3.63(m，1H)，2.84–2.52(m，1H)。LC-MS R_T4.20 min, M/z 298.1(M + H)⁺。

LCMS (2 to 98% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.20 min, ESI + found 298.1[ M + H]⁺。

Example 41: method 36

(5S,7S) -7-fluoro-5-phenyl-2- (4-pyrimidin-4-ylpyrazol-1-yl) -6, 7-dihydro-5H-pyrrolo

[1,2-b ] [1,2,4] triazole

The title compound was prepared analogously by replacing 1H-pyrazole-4-carbaldehyde with 2-4- (pyrimidin-4-yl) pyrazole. (CASRN 28648-87-5).

¹H NMR(400MHz，DMSO-d₆) δ 9.19(s, 1H), 9.14(d, J ═ 1.5Hz, 1H), 8.78(d, J ═ 5.3Hz, 1H), 8.47(s, 1H), 7.99(dd, J ═ 5.3, 1.5Hz, 1H), 7.49-7.35 (m, 3H), 7.35-7.28 (m, 2H), 6.28(ddd, J ═ 56.7, 7.2, 2.0Hz, 1H), 5.72(td, J ═ 8.0, 3.1Hz, 1H), 3.83-3.65 (m, 1H), 2.77-2.60 (m, 1H). LC-MS RT 4.52 min, M/z 348.2(M + H)⁺。

LCMS (2 to 98% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.52 min, ESI + found 348.2[ M + H%]⁺。

Example 42: method 37

(5S,7S) -2- [ 1-bicyclo [1.1.1] pentyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Diethylaminosulfur trifluoride (0.150mL, 1.08mmol) was added to 3-bicyclo [1.1.1 at room temperature]Pentyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]Methanone (40mg, 0.135mmol) in dichloromethane (2.7 mL). After 36h, additional diethylaminosulfur trifluoride (0.150mL, 1.08mmol) was added. After 12h, the reaction was poured into a separatory funnel containing saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was purified by reverse phase HPLC to give (5S,7S) -2- [ 3-bicyclo [1.1.1]Pentyl (difluoro) methyl group]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (14.6mg, 0.046mmol, 34% yield).¹H NMR(400MHz，DMSO-d₆)δ7.48–7.32(m，3H)，7.25–7.15(m，2H)，6.20(ddd，J＝56.5，7.1，1.8Hz，1H)，5.69(ddd，J＝9.1，6.9，2.9Hz，1H)，3.82–3.63(m，1H)，2.76–2.59(m，1H)，2.57(s，1H)，1.91(s，6H)。LRMS R_T5.80 min, M/z 320.1[ M + H ]]⁺。

Information on preparative HPLC: column: Gemini-NX C185 μm, (50X30mm), mobile phase: 0.1% ammonium hydroxide/water (a)/acetonitrile (B), elution procedure, gradient: 30% to 70% B, flow rate: 60 mL/min, column temperature: 25 ℃, wavelength: 220nm

Example 43: method 39

(5S,7S) -2- (2-cyclopropylethynyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Cuprous iodide (1.7mg, 0.0088mmol) was added to (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (50mg, 0.177mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (13.2mg, 0.0177mmol) and cyclopropylacetylene (0.150mL, 1.77mmol) in degassed solutions of triethylamine (0.90mL) and THF (0.90 mL). The reaction was sealed with a yellow cap and heated at 60 ℃ for 24 h. After cooling to room temperature, the reaction was filtered through a plug of Celite using isopropyl acetate. The filtrate was concentrated and the crude residue was purified by reverse phase HPLC to give (5S,7S) -2- (2-cyclopropylethynyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (4.4mg, 0.016mmol, 9.2% yield).¹H NMR(400MHz，DMSO-d₆)δ7.46–7.31(m，3H)，7.25–7.14(m，2H)，6.24–6.01(m，1H)，5.59(ddd，J＝8.3，6.9，3.0Hz，1H)，3.77–3.57(m，1H)，2.72–2.54(m，1H)，1.57(tt，J＝8.2，5.0Hz，1H)，0.95–0.87(m，2H)，0.80–0.72(m，2H)。LRMS R_T5.00 min, M/z 268.1[ M + H ]]⁺。

Information on preparative HPLC: column: Gemini-NX C185 μm, (50X30mm), mobile phase: 0.1% ammonium hydroxide/water (a)/acetonitrile (B), elution procedure, gradient: 20% to 60% B, flow rate: 60 mL/min, column temperature: 25 ℃, wavelength: 254nm

Example 44: method 40

(5S,7S) -7-fluoro-5-phenyl-2-prop-1-ynyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Potassium propynyl trifluoroborate (40mg, 0.27mmol), (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (50mg, 0.177mmol), cesium carbonate (0.173g, 0.53mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (13.2mg, 0.0177mmol) was dissolved in THF (1.5mL) and water (0.15 mL). The reaction was degassed with nitrogen for 5 minutes. The reaction was then heated at 80 ℃ for 1 h. After cooling to room temperature, the reaction was filtered through a plug of Celite using isopropyl acetate. The filtrate was evaporated and the crude residue was purified by reverse phase HPLC to give (5S,7S) -7-fluoro-5-phenyl-2-prop-1-ynyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (30.0mg, 0.124mmol, 70% yield).¹H NMR(400MHz，DMSO-d₆)δ7.47–7.30(m，3H)，7.23–7.12(m，2H)，6.24–6.03(m，1H)，5.65–5.54(m，1H)，3.78–3.56(m，1H)，2.63(ddt，J＝27.0，15.2，2.2Hz，1H)，2.05(s，3H)。LRMS R_T4.50 min, 242.1[ M + H ] M/z]⁺。

Information on preparative HPLC: column: Gemini-NX C185 μm, (50X30mm), mobile phase: 0.1% aqueous formic acid (a)/acetonitrile (B), gradient elution procedure: 20% to 60% B, flow rate: 60 mL/min, column temperature: 25 ℃, wavelength: 230nm

Examples 45 and 46: method 41

(5S,7S) -2- ((R) -bicyclo [1.1.1] pent-1-ylfluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -2- ((S) -bicyclo [1.1.1] pent-1-ylfluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Sodium borohydride (0.133g, 3.36mmol) was added to a solution of 3-bicyclo [1.1.1] pentyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanone (0.100g, 0.336mmol) in ethanol (3.4mL) at room temperature. After 20 minutes, the reaction was diluted with dichloromethane and water. Saturated aqueous ammonium chloride was added and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue submitted to the next step without further purification.

Diethylaminosulfur trifluoride (0.24mL, 1.68mmol) was added to a solution of the crude residue in dichloromethane (3.4mL) at room temperature. After 20 min, the reaction was quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over sodium sulfate, concentrated and the crude residue was purified by SFC to afford any indicated (5S,7S) -2- ((R) -bicyclo [ 1.1.1) over 2 steps]Pent-1-ylfluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (1.49mg, 0.005mmol, 1.4% yield) and (5S,7S) -2- ((S) -bicyclo [ 1.1.1)]Pent-1-ylfluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (1.96mg, 0.0065mmol, 1.9% yield). Are respectively LRMS R_T4.90 min, M/z 302.1[ M + H ]]⁺And LRMSR_T4.82 min, M/z 302.1[ M + H ]]⁺。

Preparative SFC information: column: chiralcel OX 5 μm, (250 × 21.2mm), mobile phase: carbon dioxide (a)/0.1% ammonium hydroxide/isopropanol (B), elution procedure isocratic: 12% B, flow rate: 70 mL/min, column temperature: 25 ℃, wavelength: 211nm

Preparative SFC information: column: chiralcel OX 5 μm, (250 × 21.2mm), mobile phase: carbon dioxide (a)/0.1% ammonium hydroxide/isopropanol (B), elution procedure isocratic: 12% B, flow rate: 70 mL/min, column temperature: 25 ℃, wavelength: 211 nm.

Example 47: method 42

1- [ [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ] cyclopropanecarbonitrile

Step 1: rac- (5S,7S) -2- (bromomethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a solution of (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methanol (350mg, 1.5mmol, 1.0 equiv.) in dichloromethane (10mL) was added polymer-bound triphenylphosphine (2000mg, 6.0mmol, 4.0 equiv.,. about.3 mmol/g), followed by carbon tetrabromide (746mg, 2.25mmol, 1.5 equiv.). The mixture was shaken at 230rpm for 2 h. After this time, the mixture was filtered through Celite and concentrated to give rac- (5S,7S) -2- (bromomethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (370mg, 83% yield), which was used without further purification.

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 1.15 min, ESI + observed [ M + H ] ═ 296.

Step 2: 1- [ [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ] cyclopropanecarbonitrile

A solution of lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 2.5mL, 2.0 equiv.) was diluted with tetrahydrofuran (5mL) and cooled to 0 ℃. Cyclopropanenitrile (0.184mL, 1678mg, 2.5mmol, 2.0 equiv.) was added slowly. The resulting mixture was stirred at 0 ℃ for 10 minutes, then a solution of 2- (bromomethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (370mg, 1.25mmol, 1.0 equiv.) in tetrahydrofuran (5mL) was added. The resulting mixture was stirred at 0 ℃ for 1 h. After this time, the reaction was quenched with 5% aqueous citric acid (75mL) and then extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate/heptane) to give rac- (5S,7S) -1- [ (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methyl ] cyclopropanecarbonitrile as a white solid (40mg, 11% yield).

The racemic material is further separated by chiral SFC to give any of the named:

1- [ [ (5R,7R) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as white solid][1,2,4]Triazol-2-yl]Methyl radical]Cyclopropanecarbonitrile (peak 1, SFC assay retention time 0.58 min, Chiralpak AD, isocratic 10% MeOH + 0.1% NH₄OH, 2.5 min method) (5.5mg, 2%). 1H NMR (400MHz, DMSO-d6) δ 7.46-7.29 (m, 3H), 7.24-7.13 (m, 2H), 6.16(ddd, J ═ 57.0, 7.1, 1.7Hz, 1H), 5.62(ddd, J ═ 8.8, 7.2, 2.7Hz, 1H), 3.79-3.58 (m, 1H), 2.92(s, 2H), 2.70-2.54 (m, 1H), 1.28-1.23 (m, 2H), 1.11-1.03 (m, 2H) LC-MS R_T4.27 min, M/z 283.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.27 min, ESI + observed [ M + H ] ═ 283.1.

1- [ [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as white solid][1,2,4]Triazol-2-yl]Methyl radical]Cyclopropanecarbonitrile (peak 2, SFC assay retention time 0.68 min, Chiralpak AD, isocratic 10% MeOH + 0.1% NH₄OH, 2.5 min method) (6.5mg, 2%).¹H NMR(400MHz，DMSO-d6)δ7.44–7.30(m，3H)，7.24–7.16(m，2H)，6.16(ddd，J＝57.0，7.1，1.6Hz，1H)，5.62(ddd，J＝8.6，8.0，2.7Hz，1H)，3.79–3.57(m，1H)，2.92(s，2H)，2.70–2.54(m，1H)，1.30–1.20(m，2H)，1.13–1.02(m，2H)。LC-MS R_T4.27 min, M/z 283.1(M + H)⁺。

SFC conditions (preparative): column: chiralpak AD 250 × 21.2mm i.d., 5um mobile phase: a: CO2₂B: methanol, isocratic 15% methanol for 25 minutes, flow rate: 70 mL/minClock, column temperature 40 ℃.

Example 48: method 43

2-fluoro-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] acetonitrile

To 2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]To a solution of acetonitrile (250mg, 1.0mmol, 1.0 equiv.) in tetrahydrofuran (5mL) cooled to-78 deg.C was added lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 2.58mL, 2.5 equiv.). The resulting mixture was stirred at-78 ℃ for 30 minutes, then N-fluorobenzenesulfonylimide (814mg, 2.58mmol, 2.5 equiv.) was added thereto. The cooling bath was removed and the mixture was allowed to warm slowly to room temperature over 1 h. After this time, the reaction was quenched with 5% aqueous citric acid and extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate/heptane) to give 2-fluoro-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Acetonitrile (16mg, 6% yield). 1H NMR (400MHz, methanol-d 4) δ 7.47-7.32 (m, 3H), 7.31-7.19 (m, 2H), 6.58(d, J ═ 45.7Hz, 1H), 6.10(ddd, J ═ 56.2, 7.3, 2.0Hz, 1H), 5.68-5.55 (m, 1H), 3.83-3.64 (m, 1H), 2.80(dddd, J ═ 26.6, 15.3, 3.3, 2.0Hz, 1H). LC-MS R_T1.17 min, M/z 261(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 1.17 min, ESI + observed [ M + H ] ═ 261.

Example 49: method 44

(5S,7S) -7-fluoro-2- [ (E) -2- (1-methylpyrazol-4-yl) vinyl ] -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (100mg, 0.35mmol), 1-methyl-4-vinyl-1H-pyrazole (134mg, 1.24mmol), 2, 6-di-tert-butyl-4-methylphenol (8mg, 0.04mmol), 1' -bis (diphenylphosphino) ferrocene-palladium dichloride (ii) dichloromethane complex (59mg, 0.07mmol) and triethylamine (0.59mL, 4.25mmol) in N, N-dimethylacetamide (2mL) was heated at 110 ℃ for 18H. The reaction mixture was diluted with 100ml EtOAc, washed with water, filtered through celite, and the organic layer was washed with brine. The crude product was purified by column chromatography, washed with 0-10% MeOH/DCM, and further purified by preparative HPLC (Gemini-NXC 1850 × 30mm, 5um, 20-60% 0.1% aqueous formic acid/acetonitrile) to give the final product as a white solid (6mg, 5%).¹H NMR(400MHz，DMSO-d₆)δ7.96(s，1H)，7.76(s，1H)，7.46–7.29(m，4H)，7.27–7.19(m，2H)，6.77(d，J＝16.3Hz，1H)，6.14(ddd，J＝57.1，7.1，1.8Hz，1H)，5.58(ddd，J＝8.3，7.0，2.8Hz，1H)，3.82(s，3H)，3.77–3.59(m，1H)，2.71–2.50(m，1H)。LC-MS R_T4.24 min, M/z 310.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.24 min, ESI + observed [ M + H ] ═ 310.1

Example 50: method 45

(5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (200mg, 0.71mmol), potassium vinyltrifluoroborate (130mg, 0.92mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (59mg, 0.07mmol) and cesium carbonate (693mg, 2.13mmol) in 1, 4-dioxane (5mL) and water (0.5mL) was heated at 90 ℃ under nitrogen atmosphere for 16 h. After cooling, the mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sulfurThe sodium salt was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate/petroleum ether) to give (5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (133mg, 82%).¹H NMR(400MHz，DMSO-d₆)δ7.45–7.31(m，3H)，7.26–7.18(m，2H)，6.65(dd，J＝17.5，11.0Hz，1H)，6.21(dd，J＝7.1，1.8Hz，0H)，6.13(dd，J＝17.5，1.8Hz，1H)，6.07(dd，J＝7.1，1.8Hz，0H)，5.59(ddd，J＝8.4，6.9，2.9Hz，1H)，5.51(dd，J＝11.0，1.9Hz，1H)，3.68(dddd，J＝26.0，15.4，8.4，7.1Hz，1H)，2.63(dddd，J＝26.4，15.2，3.0，1.8Hz，1H)。LC-MS R_T4.23 min, M/z 230.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.23 min, ESI + observed [ M + H ] ═ 230.1

Example 51: method 46

2- [ (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methoxy ] acetonitrile step 1: rac- (5S,7S) - (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methanol

To [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]To a solution of triazole-2-carboxylic acid ethyl ester (1000mg, 3.63mmol, 1.0 equiv.) in THF (25mL) cooled to 0 deg.C was added lithium borohydride (2M in tetrahydrofuran, 1.91mL, 3.81mmol, 1.05 equiv.). The ice bath was removed and the mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was poured into 5% aqueous citric acid (100 mL). The mixture was extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give rac- (5S,7S) - (7) as a white solid-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b [ ]][1,2,4]Triazol-2-yl) methanol, used without further purification (805mg, 95% yield). LC-MS R_T0.88 min, 234.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 0.88 min, ESI + observed [ M + H ] ═ 234.1

Step 2: 2- [ (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methoxy ] acetonitrile

To rac- (5S,7S) - (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]To a solution of triazol-2-yl) methanol (60mg, 0.26mmol) in tetrahydrofuran (1mL) was added NaH 60% (13mg, 0.33 mmol). The resulting mixture was stirred at room temperature for half an hour, and bromoacetonitrile (0.025mL, 0.36mmol) in tetrahydrofuran (0.5mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 3 h. After this time, the reaction was quenched with water and extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated. The resulting residue was purified by preparative HPLC (Gemini-NX C1850 x30mm, 5um, 10-60% 0.1% aqueous formic acid/acetonitrile) to give the final product as a white solid (41mg, 58%).¹H NMR(400MHz，DMSO-d₆)δ7.45–7.31(m，3H)，7.26–7.18(m，2H)，6.16(ddd，J＝56.8，7.1，1.8Hz，1H)，5.61(ddd，J＝8.4，6.9，2.9Hz，1H)，4.60(s，2H)，4.53(s，2H)，3.69(dddd，J＝26.0，15.4，8.5，7.1Hz，1H)，2.65(dddd，J＝26.5，15.2，3.0，1.8Hz，1H)。LC-MS R_T3.96 min, 273.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.96 min, ESI + observed [ M + H ] ═ 273.1

Example 52: method 45

(5S,7S) -2-allyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(7mg, 8% yield).¹H NMR(400MHz，DMSO-d₆)δ7.45–7.30(m，3H)，7.24–7.16(m，2H)，6.11(ddd，J＝57.1，7.1，1.6Hz，1H)，6.01–5.90(m，1H)，5.55(ddd，J＝8.3，7.2，2.8Hz，1H)，5.20–5.01(m，2H)，3.65(dddd，J＝26.4，15.4，8.4，7.1Hz，1H)，3.44(dt，J＝6.7，1.5Hz，2H)，2.60(dddd，J＝26.3，15.3，2.8，1.7Hz，1H).LC-MS R_T4.32 min, M/z 244.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.32 min, ESI + observed [ M + H ] ═ 244.1

Example 53: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-3-carbonitrile

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (15mg, 0.053mmol), cuprous iodide (2mg, 0.011mmol), (1S,2S) -N¹,N²A mixture of-dimethylcyclohexane-1, 2-diamine (8mg, 0.053mmol), cesium carbonate (52mg, 0.16mmol) and 1H-pyrazole-3-carbonitrile (52mg, 0.53mmol) in 1, 4-dioxane (0.5mL) was heated in a sealed tube at 140 ℃ under microwave for 3H. After cooling, the mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini-NX C1850 x30mm, 5um, 20-60% 0.1% aqueous formic acid/acetonitrile) to give the final product as a white solid (4mg, 26%).¹H NMR(400MHz，DMSO-d₆)¹H NMR(400MHz，DMSO-d₆)δ8.69(d，J＝2.7Hz，1H)，7.51–7.30(m，3H)，7.38–7.17(m，3H)，6.23(dddd，J＝56.6，38.4，7.2，2.0Hz，1H)，5.68(dtd，J＝31.1，7.9，3.1Hz，1H)，3.89–3.55(m，1H)，2.80–2.52(m，1H)。LC-MS R_T4.81 min, M/z 295.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.81 min, ESI + observed [ M + H ] ═ 295.1

Example 54: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-4-carbonitrile

(8mg, 15% yield).¹H NMR(400MHz，DMSO-d₆)δ9.27(s，1H)，8.39(s，1H)，7.52–7.36(m，3H)，7.40–7.26(m，2H)，6.27(ddd，J＝56.5，7.3，2.0Hz，1H)，5.72(td，J＝8.0，3.1Hz，1H)，3.73(dddd，J＝24.9，15.4，8.5，7.3Hz，1H)，2.76–2.58(m，1H)。LC-MS R_T4.52 min, M/z 295.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.52 min, ESI + observed [ M + H ] ═ 295.1

Example 55: method 44

3- [ [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methylene ] cyclobutanenitrile

(21mg, 10% yield).¹H nmR(400MHz，DMSO-d6)δ7.64–7.51(m，0H)，7.48–7.30(m，3H)，7.19(dd，J＝7.8，1.7Hz，2H)，6.25–6.02(m，2H)，5.63–5.51(m，1H)，3.66(dddd，J＝26.6，15.5，8.5，7.1Hz，1H)，3.55–3.43(m，2H)，3.30–3.10(m，3H)，2.73–2.53(m，1H)。LC-MSR_T4.57 min, M/z 295.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.57 min, ESI + observed [ M + H ] ═ 295.1

Example 56: method 47

(5S,7S) -7-fluoro-5-phenyl-2- [4- (trifluoromethyl) pyrazol-1-yl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(14mg, 19% yield).¹H NMR(400MHz，DMSO-d₆)δ9.07(s，1H)，8.28(s，1H)，7.42(ddt，J＝14.6，7.7，6.2Hz，3H)，7.35–7.25(m，2H)，6.40–6.16(m，1H)，5.73(td，J＝7.9，3.1Hz，1H)，3.83–3.62(m，1H)，2.77–2.58(m，1H)。LC-MS R_T5.39 min, 338.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.39 min, ESI + observed [ M + H ] ═ 338.1

Example 57: the method 47:

(5S,7S) -7-fluoro-2- (4-methoxypyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(20mg, 30% yield).¹H NMR(400MHz，DMSO-d₆)δ8.05(s，1H)，7.60(s，1H)，7.42(q，J＝6.2Hz，3H)，7.31–7.12(m，2H)，6.22(ddd，J＝56.9，7.3，1.9Hz，1H)，5.65(td，J＝8.0，3.0Hz，1H)，3.72–3.56(m，1H)，2.64(ddt，J＝26.7，15.1，2.4Hz，1H)。LC-MS R_T4.47 min, 300.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.47 min, ESI + observed [ M + H ] ═ 300.1

Example 58: method 47

(5S,7S) -7-fluoro-2- (4-fluoropyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(29mg, 47% yield).¹H NMR(400MHz，DMSO-d6)δ8.53(dd，J＝4.6，0.8Hz，1H)，7.91(dd，J＝4.2，0.8Hz，1H)，7.48–7.25(m，5H)，6.24(ddd，J＝56.7，7.3，1.9Hz，1H)，5.68(td，J＝8.0，3.0Hz，1H)，3.71(dddd，J＝25.1，15.4，8.3，7.2Hz，1H)，2.80–2.55(m，1H)。LC-MS R_T4.62 min, M/z 288.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.62 min, ESI + observed [ M + H ] ═ 288.1

Example 59: method 47

(5S,7S) -2- (4-ethylpyrazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(21mg, 33% yield).¹H NMR(400MHz，DMSO-d₆)δ8.12(d，J＝1.0Hz，1H)，7.64(s，1H)，7.47–7.34(m，3H)，7.38–7.21(m，2H)，6.23(ddd，J＝56.8，7.2，1.9Hz，1H)，5.66(td，J＝8.0，2.9Hz，1H)，3.70(dddd，J＝25.3，15.4，8.4，7.2Hz，1H)，2.64(dddd，J＝26.7，15.2，3.0，1.9Hz，1H)，2.50–2.42(m，2H)，1.17(t，J＝7.5Hz，3H)。LC-MS R_T5.03 min, M/z 298.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.03 min, ESI + observed [ M + H ] ═ 298.1

Example 60: method 47

(5S,7S) -2- (4-Chloropyrazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(14mg, 22% yield).¹H NMR(400MHz，DMSO-d₆)δ8.63(s，1H)，7.93(s，1H)，7.51–7.35(m，3H)，7.33–7.25(m，2H)，6.25(ddd，J＝56.7，7.3，1.9Hz，1H)，5.69(td，J＝7.9，3.1Hz，1H)，3.72(dddd，J＝25.1，15.4，8.4，7.2Hz，1H)，2.74–2.58(m，1H)。LC-MS R_T5.04 min, 304.0(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.04 min, ESI + observed [ M + H ] ═ 304.0

Example 61: method 48

(5S,7S) -7-fluoro-2- (1-methylimidazol-2-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]A mixture of triazole (60mg, 0.21mmol), 1-methyl-2- (tributylstannyl) -1H-imidazole (250mg, 0.64mmol), bis (triphenylphosphine) palladium (II) dichloride (15mg, 0.021mmol) in N, N-dimethylacetamide (1.5mL) was heated at 100 ℃ overnight. The reaction mixture was diluted with 100ml EtOAc, washed with water and filtered

Filter, separate the layers, and wash the organic layer with brine. The crude product was further purified by preparative HPLC (Gemini-NX C1850 x30mm, 5um, 5-50% 0.1% aqueous ammonium hydroxide solution/acetonitrile) to give the product as a white solid (17mg, 29%).¹H NMR(500MHz，DMSO-d6)δ7.46–7.40(m，2H)，7.40–7.32(m，1H)，7.31(s，1H)，7.29–7.24(m，2H)，6.99(s，1H)，6.24(ddd，J＝56.8，7.1，1.6Hz，1H)，5.71(td，J＝8.6，2.7Hz，1H)，3.74(dddd，J＝26.3，15.4，8.3，7.2Hz，1H)，3.34(s，2H)，2.75–2.63(m，1H)。LC-MS R_T2.78 min, 284.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 2.78 min, ESI + observed [ M + H ] ═ 284.1

Example 62: method 47

(5S,7S) -7-fluoro-5-phenyl-2- [4- (trifluoromethyl) imidazol-1-yl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(30mg, 72% yield).¹H NMR(400MHz，DMSO-d6)δ8.56–8.51(m，1H)，8.41(p，J＝1.3Hz，1H)，7.48–7.34(m，3H)，7.39–7.27(m，2H)，6.27(ddd，J＝56.5，7.3，2.0Hz，1H)，5.71(td，J＝7.9，3.1Hz，1H)，3.74(dddd，J＝24.9，15.5，8.4，7.3Hz，1H)，2.75–2.58(m，1H)。LC-MS R_T5.39 min, 338.1(M + H) M/z⁺。

Example 63: method 49

(5S,7S) -7-fluoro-2- (5-methylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: 1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) -5-methyl-1H-pyrazol-3-amine and 1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) -3-methyl-1H-pyrazol-5-amine

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (120mg, 0.43mmol), cuprous iodide (97mg, 0.51mmol), (1S,2S) -N¹,N²A mixture of-dimethylcyclohexane-1, 2-diamine (484mg, 3.40mmol), cesium carbonate (416mg, 1.28mmol) and 3-amino-5-methylpyrazole (426mg, 4.25mmol) in 1, 4-dioxane (2mL) was heated in a sealed tube at 140 ℃ under microwave for 3 h. After cooling, the mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Residue is passed throughChiral SFC was purified to give two peaks:

1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a white solid][1,2,4]Triazol-2-yl) -5-methyl-1H-pyrazol-3-amine (peak 1, 9mg, 7%).¹H NMR(500MHz，DMSO-d6)δ7.42(dd，J＝8.0，6.6Hz，2H)，7.40–7.34(m，1H)，7.27–7.22(m，2H)，6.20(ddd，J＝57.0，7.1，1.6Hz，1H)，5.63(td，J＝8.0，2.7Hz，1H)，5.54(s，1H)，4.95(s，2H)，3.74–3.60(m，1H)，2.61(ddt，J＝26.4，15.1，1.9Hz，1H)，2.36(s，3H)。LC-MS R_T3.89 min, M/z 299.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.89 min, ESI + observed [ M + H ] ═ 299.1.

1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a white solid][1,2,4]Triazol-2-yl) -3-methyl-1H-pyrazol-5-amine (peak 2, 12mg, 10%).¹H NMR(500MHz，DMSO-d6)δ7.46–7.40(m，2H)，7.40–7.36(m，1H)，7.30–7.24(m，2H)，6.28(dd，J＝7.1，1.7Hz，1H)，6.17(d，J＝5.8Hz，3H)，5.64(td，J＝8.1，2.8Hz，1H)，5.21(s，1H)，3.77–3.62(m，1H)，2.70–2.57(m，1H)，2.02(s，3H)。LC-MS R_T3.94 min, M/z 299.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.94 min, ESI + observed [ M + H ] ═ 299.1.

SFC conditions (preparative): column: PIC 200Achiral 150x30mm, 5um mobile phase: a: CO2₂B: 0.1% ammonium hydroxide/methanol, isocratic 20% 0.1% ammonium hydroxide/methanol for 5min X4 cycles, flow rate: 150 mL/min, column temperature 40 ℃.

Step 2: (5S,7S) -7-fluoro-2- (5-methylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To 1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]To a solution of triazol-2-yl) -3-methyl-1H-pyrazol-5-amine (9mg, 0.030mmol) in tetrahydrofuran (0.5mL) was added isoamyl nitrite (11mg, 0.012 mmol). The resulting mixture was heated at 70 ℃ for 4 h. After cooling, the mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Gemini-NX C1850 x30mm, 5um, 20-60% 0.1% aqueous ammonium hydroxide solution/acetonitrile) to give the final product as a white solid (2.7mg, 31%).¹H NMR(400MHz，DMSO-d6)δ7.60(d，J＝1.6Hz，1H)，7.48–7.33(m，3H)，7.31–7.24(m，2H)，6.42–6.12(m，2H)，5.72(td，J＝7.9，2.9Hz，1H)，3.72(dddd，J＝25.7，15.4，8.4，7.2Hz，1H)，2.74–2.56(m，1H)，2.42(s，3H)。LC-MS R_T4.61 min, 284.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.61 min, ESI + observed [ M + H ] ═ 284.1

Example 64: method 49

(5S,7S) -7-fluoro-5-phenyl-2- [3- (trifluoromethyl) pyrazol-1-yl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(20mg, 58% yield).¹H NMR(400MHz，DMSO-d6)δ8.63(dq，J＝2.2，1.0Hz，1H)，7.53–7.36(m，3H)，7.35–7.25(m，2H)，7.06(d，J＝2.6Hz，1H)，6.28(ddd，J＝56.7，7.2，2.0Hz，1H)，5.71(td，J＝8.1，3.2Hz，1H)，3.74(dddd，J＝24.8，15.5，8.4，7.3Hz，1H)，2.78–2.60(m，1H)。LC-MS R_T5.64 min, 338.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.64 min, ESI + observed [ M + H ] ═ 338.1

Example 65: method 47

5-amino-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -3-methyl-pyrazole-4-carbonitrile

(27mg, 10% yield).¹H NMR(500MHz，DMSO-d6)δ7.50(s，2H)，7.45–7.36(m，3H)，7.30–7.27(m，2H)，6.33–6.14(m，1H)，5.90(s，0H)，5.67(td，J＝8.0，3.0Hz，1H)，3.78–3.62(m，1H)，2.72–2.59(m，1H)，2.14(s，3H)。LC-MS R_T1.13 min, 324.0(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 1.13 min, ESI + observed [ M + H ] ═ 324.0

Example 66: method 47

(5S,7S) -7-fluoro-2-imidazol-1-yl-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(42mg, 51% yield).¹H NMR(400MHz，DMSO-d₆)δ8.30(t，J＝1.1Hz，1H)，7.72(q，J＝1.3Hz，1H)，7.48–7.32(m，3H)，7.36–7.17(m，2H)，7.15–7.08(m，1H)，6.24(ddd，J＝56.6，7.2，1.9Hz，1H)，5.68(td，J＝8.0，3.1Hz，1H)，3.72(dddd，J＝25.0，15.4，8.4，7.2Hz，1H)，2.64(dddd，J＝26.9，15.1，3.1，2.0Hz，1H)。LC-MS R_T3.30 min, M/z 270.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.30 min, ESI + observed [ M + H ] ═ 270.1

Example 67: method 47

(5S,7S) -7-fluoro-2- (2-methylimidazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(10mg, 12% yield))。¹H NMR(400MHz，DMSO-d₆)δ7.54(d，J＝1.5Hz，1H)，7.48–7.31(m，3H)，7.32–7.23(m，2H)，6.91(d，J＝1.6Hz，1H)，6.25(ddd，J＝56.6，7.2，1.9Hz，1H)，5.71(td，J＝8.0，3.0Hz，1H)，3.71(dddd，J＝25.6，15.4，8.4，7.1Hz，1H)，2.72–2.55(m，1H)，2.55–2.50(m，3H)。LC-MS R_T2.95 min, 284.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 2.95 min, ESI + observed [ M + H ] ═ 284.1

Example 68: method 47

(5S,7S) -7-fluoro-5-phenyl-2- (1,2, 4-triazol-1-yl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(2mg, 3% yield).

LC-MS R_T4.01 min, 271.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.01 min, ESI + observed [ M + H ] ═ 271.1

Example 69: method 47

(5S,7S) -2- (2-Chloroimidazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(2mg, 3% yield).¹H NMR(400MHz，DMSO-d₆)δ7.73(d，J＝1.7Hz，1H)，7.51–7.34(m，4H)，7.32–7.24(m，2H)，7.09(d，J＝1.7Hz，1H)，6.42–6.18(m，1H)，5.75(ddd，J＝8.3，7.2，3.0Hz，1H)，3.73(dddd，J＝25.6，15.4，8.5，7.2Hz，1H)，2.75–2.55(m，1H)。LC-MS R_T4.50 min, 304.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.50 min, ESI + observed [ M + H ] ═ 304.1

Example 70: method 47

(5S,7S) -2- (4, 5-Dimethylimidazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(53mg, 63% yield).¹H NMR(400MHz，DMSO-d6)δ7.97(s，1H)，7.47–7.33(m，3H)，7.30–7.23(m，2H)，6.24(ddd，J＝56.6，7.2，1.9Hz，1H)，5.70(td，J＝7.9，2.9Hz，1H)，3.70(dddd，J＝25.7，15.4，8.4，7.2Hz，1H)，2.63(dddd，J＝26.6，15.2，3.0，1.9Hz，1H)，2.29(d，J＝0.9Hz，3H)，2.08(d，J＝0.9Hz，3H)。LC-MS R_T3.21 min, M/z 298.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.21 min, ESI + observed [ M + H ] ═ 298.2

Example 71: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -3-methyl-imidazol-2-one

(29mg, 46% yield).¹H NMR(400MHz，DMSO-d6)δ7.47–7.33(m，3H)，7.37–7.21(m，2H)，6.87(d，J＝3.2Hz，1H)，6.71(d，J＝3.2Hz，1H)，6.19(ddd，J＝56.9，7.2，1.8Hz，1H)，5.64(td，J＝8.0，2.9Hz，1H)，3.68(dddd，J＝25.7，15.3，8.4，7.1Hz，1H)，3.15(s，3H)，2.61(dddd，J＝26.6，15.3，3.0，1.8Hz，1H)。LC-MS R_T3.78 min, 300.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.78 min, ESI + observed [ M + H ] ═ 300.1

Example 72: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] indazole-4-carbonitrile

(43mg, 59% yield).¹H NMR(500MHz，DMSO-d6)δ8.68(d，J＝0.8Hz，1H)，8.60(d，J＝8.7Hz，1H)，7.97–7.92(m，1H)，7.77(dd，J＝8.6，7.3Hz，1H)，7.48–7.42(m，2H)，7.42–7.37(m，1H)，7.37–7.31(m，2H)，6.32(ddd，J＝56.7，7.2，1.8Hz，1H)，5.77(td，J＝8.0，2.9Hz，1H)，3.84–3.69(m，1H)，2.76–2.65(m，1H)。LC-MS R_T5.54 min, 345.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.54 min, ESI + observed [ M + H ] ═ 345.1

Example 73: method 47

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] indazole

(20mg, 29% yield).¹H NMR(500MHz，DMSO-d6)δ8.43(d，J＝0.7Hz，1H)，8.27(dd，J＝8.5，0.8Hz，1H)，7.91(d，J＝8.0Hz，1H)，7.58(ddd，J＝8.3，7.0，1.0Hz，1H)，7.48–7.42(m，2H)，7.42–7.36(m，1H)，7.36–7.30(m，3H)，6.31(ddd，J＝56.9，7.1，1.7Hz，1H)，5.74(td，J＝8.0，2.8Hz，1H)，3.83–3.68(m，1H)，2.75–2.62(m，1H)。LC-MS R_T5.47 min, 320.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.47 min, ESI + observed [ M + H ] ═ 320.1

Example 74: method 49

(5S,7S) -7-fluoro-2- (5-methyl-1, 2, 4-triazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1(13mg, 85% yield).¹H NMR(500MHz，DMSO-d6)δ7.46–7.32(m，3H)，7.30–7.25(m，2H)，7.01(s，2H)，6.29-5.66(m，1H)，3.83–3.61(m，1H)，2.71–2.59(m，1H)，2.08(s，3H)。LC-MS R_T3.66 min, 300.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.66 min, ESI + observed [ M + H ] ═ 300.1

Step 2(3mg, 22% yield). LC-MS R_T4.03 min, M/z 285.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.03 min, ESI + observed [ M + H ] ═ 285.1

Example 75: method 47

(5S,7S) -2- (4-Chloroimidazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(17mg, 23% yield).¹H NMR(400MHz，DMSO-d6)δ8.32(d，J＝1.5Hz，1H)，7.87(d，J＝1.5Hz，1H)，7.50–7.34(m，3H)，7.33–7.25(m，2H)，6.25(ddd，J＝56.7，7.2，2.0Hz，1H)，5.68(td，J＝7.9，3.1Hz，1H)，3.72(dddd，J＝24.8，15.4，8.4，7.3Hz，1H)，2.64(dddd，J＝27.0，15.1，3.1，1.9Hz，1H)。LC-MS R_T4.99 min, 304.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.99 min, ESI + observed [ M + H ] ═ 304.1

Example 76: method 47

(5S,7S) -7-fluoro-2- (4-fluoroimidazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(25mg, 35% yield).¹H NMR(400MHz，DMSO-d6)δ8.11(t，J＝1.7Hz，1H)，7.50(dd，J＝8.1，1.7Hz，1H)，7.47–7.35(m，3H)，7.33–7.25(m，2H)，6.24(ddd，J＝56.5，7.3，2.0Hz，1H)，5.68(td，J＝8.0，3.1Hz，1H)，3.72(dddd，J＝24.9，15.4，8.4，7.3Hz，1H)，2.64(dddd，J＝27.0，15.1，3.1，2.0Hz，1H)。LC-MS R_T4.84 min, M/z 288.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.84 min, ESI + observed [ M + H ] ═ 288.1

Example 77: method 50

2- [1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazol-4-yl ] acetonitrile

Step 1: (1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) -1H-pyrazol-4-yl) methanol

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (300mg, 1.06mmol), cuprous iodide (1064mg, 10.63mmol), (1S,2S) -N¹,N²A mixture of-dimethylcyclohexane-1, 2-diamine (1210mg, 8.51mmol), cesium carbonate (1039mg, 3.19mmol) and (1H-pyrazol-4-yl) methanol (1064mg, 10.63mmol) in 1, 4-dioxane (2.5mL) was heated in a sealed tube under microwave at 140 ℃ for 3H. After cooling, the mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% MeOH/isopropyl acetate) to afford the final product as a white solid (169mg, 53%). LC-MS R_T0.92 point ofClock, M/z 300.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 2 min) retention time 0.92 min, ESI + observed [ M + H ] ═ 300.1

Step 2: 2- [1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazol-4-yl ] acetonitrile

To (1- ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) -1H-pyrazol-4-yl) methanol (50mg, 0.17mmol) in DCM (1mL) cooled to 0 deg.C was added trimethylamine (0.09mL, 0.67mmol) followed by methanesulfonyl chloride (0.017mL, 0.22 mmol). The resulting mixture was warmed to room temperature and stirred at room temperature for 3 h. After this time, the reaction was quenched with water and extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated. The resulting residue was dissolved in DMF (1mL) and sodium cyanide (16mg, 0.33mmol) was added. The mixture was stirred at 50 ℃ for 3 h. The reaction was quenched with water and extracted with isopropyl acetate (3 × 50 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate/heptane) to give the final product as a white solid (7mg, 14%).¹H NMR(400MHz，DMSO-d₆)δ8.36(q，J＝0.9Hz，1H)，7.79(d，J＝0.7Hz，1H)，7.48–7.33(m，3H)，7.33–7.25(m，2H)，6.24(ddd，J＝56.7，7.2，1.9Hz，1H)，5.68(td，J＝8.0，3.0Hz，1H)，3.97–3.86(m，2H)，3.83–3.56(m，1H)，2.65(dddd，J＝26.9，15.2，3.1，1.9Hz，1H).LC-MS R_T4.42 min, M/z 309.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.42 min, ESI + observed [ M + H ] ═ 309.1

Example 78: method 47

1- [1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazol-4-yl ] ethanone

(13mg, 17% yield).¹H NMR(400MHz，DMSO-d₆)δ9.04(s，1H)，8.18(s，1H)，7.48–7.37(m，3H)，7.34–7.26(m，2H)，6.43–6.16(m，1H)，5.71(td，J＝7.9，3.1Hz，1H)，3.83–3.63(m，1H)，2.76–2.63(m，1H)，2.47(s，3H)。LC-MS R_T4.56 min, 312.1(M + H) M/z⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.56 min, ESI + observed [ M + H ] ═ 312.1

Example 79: method 47

(5S,7S) -2- (4-cyclopropylpyrazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(28mg, 36% yield).¹H NMR(400MHz，DMSO-d6)δ8.09(d，J＝0.7Hz，1H)，7.59(d，J＝0.8Hz，1H)，7.47–7.35(m，3H)，7.37–7.24(m，2H)，6.22(ddd，J＝56.8，7.2，1.9Hz，1H)，5.65(td，J＝8.0，3.0Hz，1H)，3.70(dddd，J＝25.3，15.4，8.4，7.2Hz，1H)，2.63(dddd，J＝26.8，15.2，3.0，1.9Hz，1H)，1.76(tt，J＝8.4，5.1Hz，1H)，0.91–0.77(m，2H)，0.67–0.55(m，2H)。LC-MS R_T5.40 min, M/z 310.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.40 min, ESI + observed [ M + H ] ═ 310.2

Example 80: method 47

(5S,7S) -7-fluoro-2- (4-methanesulfonylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(4mg, 4% yield).¹H NMR(400MHz，DMSO-d6)δ8.98(s，1H)，8.23(s，1H)，7.48–7.34(m，3H)，7.34–7.26(m，2H)，6.28(ddd，J＝56.5，7.3，1.9Hz，1H)，5.73(td，J＝7.9，3.1Hz，1H)，3.83–3.64(m，1H)，2.76–2.60(m，1H)。LC-MS R_T4.45 min, M/z 348.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.45 min, ESI + observed [ M + H ] ═ 348.1

Example 81: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole

(11mg, 15% yield).¹H NMR(400MHz，DMSO-d₆)δ8.26–8.13(m，2H)，7.75(ddd，J＝8.3，7.1，1.1Hz，1H)，7.57(ddd，J＝8.2，7.0，1.1Hz，1H)，7.54–7.33(m，6H)，6.36(ddd，J＝56.5，7.2，2.0Hz，1H)，5.82(td，J＝7.9，3.0Hz，1H)，3.80(dddd，J＝25.1，15.4，8.4，7.2Hz，1H)，2.82–2.66(m，1H)。LC-MS R_T5.29 min, M/z 321.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.29 min, ESI + observed [ M + H ] ═ 321.1

Example 82: method 47

5-chloro-1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole

(10mg, 10% yield).¹H NMR(400MHz，DMSO-d6)δ8.48–8.09(m，2H)，7.70(ddd，J＝66.7，8.8，1.9Hz，1H)，7.51–7.33(m，5H)，6.50–6.23(m，1H)，5.91–5.74(m，1H)，3.79(dddd，J＝25.3，15.4，8.2，7.1Hz，1H)，2.85–2.63(m，1H)。LC-MS R_T5.81 min, M/z 355.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.81 min, ESI + observed [ M + H ] ═ 355.1

Example 83: method 47

3- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] triazolo [4,5-c ] pyridine

(2mg, 2% yield). LC-MS R_T4.27 min, M/z 322.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.27 min, ESI + observed [ M + H ] ═ 322.2

Example 84: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazolo [4,3-b ] pyridine

(33mg, 36% yield).¹H NMR(500MHz，DMSO-d6)δ8.70(dd，J＝4.4，1.3Hz，1H)，8.67(d，J＝0.7Hz，1H)，8.61(dd，J＝8.5，0.9Hz，1H)，7.61(dd，J＝8.6，4.4Hz，1H)，7.45(dd，J＝7.9，6.6Hz，2H)，7.42–7.36(m，1H)，7.36–7.31(m，2H)，6.31(ddd，J＝56.8，7.2，1.7Hz，1H)，5.75(td，J＝8.0，2.9Hz，1H)，3.76(ddt，J＝25.3，15.4，7.4Hz，1H)，2.69(ddt，J＝26.7，15.1，2.0Hz，1H)。LC-MS R_T4.51 min, M/z 321.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.51 min, ESI + observed [ M + H ] ═ 321.2

Example 85: method 47

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole-5-carbonitrile

(2mg, 2% yield). LC-MS R_T5.49 min, M/z 346.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.49 min, ESI + observed [ M + H ] ═ 346.1

Example 86: method 47

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -4,5,6, 7-tetrahydrobenzotriazole

(2mg, 2% yield). LC-MS R_T5.16 min, M/z 325.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.16 min, ESI + observed [ M + H ] ═ 325.2

Example 87: method 47

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazolo [3,4-c ] pyridine

(34mg, 38% yield).¹H NMR(400MHz，DMSO-d₆)δ9.63(d，J＝1.1Hz，1H)，8.58(d，J＝0.8Hz，1H)，8.46(d，J＝5.5Hz，1H)，7.93(dd，J＝5.5，1.3Hz，1H)，7.50–7.31(m，5H)，6.33(ddd，J＝56.7，7.2，1.9Hz，1H)，5.77(td，J＝8.0，3.0Hz，1H)，3.77(dddd，J＝25.3，15.4，8.3，7.1Hz，1H)，2.71(dddd，J＝26.7，15.1，3.0，1.9Hz，1H)。LC-MS R_T4.02 min, M/z 321.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.02 min, ESI + observed [ M + H ] ═ 321.2

Example 88: method 47

5-methyl-1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole

(16mg, 17% yield).¹H NMR(400MHz，DMSO-d₆)δ8.08(dd，J＝10.3，8.4Hz，1H)，7.99(dq，J＝9.6，1.2Hz，1H)，7.65–7.32(m，6H)，6.36(ddt，J＝56.5，7.3，2.0Hz，1H)，5.87–5.77(m，1H)，3.79(ddddd，J＝25.0，15.5，8.4，7.2，1.3Hz，1H)，2.82–2.66(m，1H)，2.55(d，J＝0.9Hz，3H)。LC-MS R_T5.78 min, M/z 335.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.78 min, ESI + observed [ M + H ] ═ 335.2

Example 89: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazolo [4,3-c ] pyridine

(46mg, 50% yield).¹H NMR(400MHz，DMSO-d6)δ9.23(d，J＝1.2Hz，1H)，8.65(d，J＝0.9Hz，1H)，8.58(d，J＝5.9Hz，1H)，8.15(dt，J＝6.0，1.1Hz，1H)，7.51–7.36(m，3H)，7.36–7.29(m，2H)，6.32(ddd，J＝56.7，7.2，1.9Hz，1H)，5.76(td，J＝7.9，3.0Hz，1H)，3.76(dddd，J＝25.3，15.4，8.4，7.2Hz，1H)，2.84–2.58(m，1H)。LC-MS R_T3.13 min, M/z 321.2(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 3.13 min, ESI + observed [ M + H ] ═ 321.2

Example 90: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] triazolo [4,5-c ] pyridine

(3mg, 2% yield). LC-MS R_T4.36 min, M/z 322.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.36 min, ESI + observed [ M + H ] ═ 322.1

Example 91: method 47

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -5-methyl-pyrazole-3-carbonitrile

(7mg, 5% yield).¹H NMR(500MHz，DMSO-d6)δ7.47–7.41(m，2H)，7.41–7.35(m，1H)，7.32–7.26(m，2H)，7.03(d，J＝0.8Hz，1H)，6.30(ddd，J＝56.4，7.2，1.9Hz，1H)，5.76(td，J＝8.1，3.0Hz，1H)，3.82–3.66(m，1H)，2.75–2.63(m，1H)，2.47(d，J＝0.6Hz，3H)。LC-MSR_T5.05 min, M/z 309.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 5.05 min, ESI + observed [ M + H ] ═ 309.1

Example 92: method 49

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -3-methyl-pyrazole-4-carbonitrile

(10mg, 35% yield).¹H NMR(400MHz，DMSO-d6)δ9.14(s，1H)，7.48–7.34(m，3H)，7.33–7.25(m，2H)，6.26(ddd，J＝56.5，7.2，2.0Hz，1H)，5.69(td，J＝8.0，3.1Hz，1H)，3.72(dddd，J＝24.9，15.5，8.3，7.2Hz，1H)，2.67(dddd，J＝27.0，15.2，3.1，2.0Hz，1H)，2.36(s，3H)。LC-MS R_T4.99 min, M/z 309.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.99 min, ESI + observed [ M + H ] ═ 309.1

Example 93: method 49

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -5-methyl-pyrazole-4-carbonitrile

(8mg, 29% yield).¹H NMR(400MHz，DMSO-d6)δ8.25(s，1H)，7.48–7.34(m，3H)，7.33–7.21(m，2H)，6.29(ddd，J＝56.4，7.2，2.0Hz，1H)，5.75(ddd，J＝8.3，7.2，3.1Hz，1H)，3.73(dddd，J＝25.2，15.4，8.4，7.2Hz，1H)，2.76–2.61(m，1H)，2.59(s，3H)。LC-MS R_T4.91 min, M/z 309.1(M + H)⁺。

LCMS (5 to 95% acetonitrile/water + 0.1% formic acid over 10 min) retention time 4.91 min, ESI + observed [ M + H ] ═ 309.1

Example 94: method 34

(5S,7S) -2- (cyclobutylmethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

(16.9mg, 63% yield). 1H NMR (400MHz, DMSO-d6) δ 7.50-7.29 (m, 3H), 7.25-7.10 (m, 2H), 6.09(ddd, J ═ 57.1, 7.1, 1.7Hz, 1H), 5.54(ddd, J ═ 8.4, 7.1, 2.8Hz, 1H), 4.09(d, J ═ 5.4Hz, 1H), 3.64(dddd, J ═ 26.7, 15.3, 8.4, 7.0Hz, 1H), 3.17(d, J ═ 4.0Hz, 1H), 2.78-2.55 (m, 3H), 2.05-1.96 (m, 1H), 1.88-1.62 (m, 3H), 1.06(t, J ═ 6.4, 1H). LC-MS R_T5.08 min, M/z 272.1(M + H)⁺。

Examples 95 and 96: method 51

(5S,7S) -7-fluoro-5-phenyl-2- [ (1S,2S) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -7-fluoro-5-phenyl-2- [ (1R,2R) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: 4,4,5, 5-tetramethyl-2- [ (1R,2R) -2-methylcyclopropyl ] -1,3, 2-dioxaborolan

To a solution of diethyl zinc (23.8mL, 23.8mmol, 1M in toluene) in dichloromethane (10mL) was added a solution of trifluoroacetic acid (2714mg, 23.8mmol) in dichloromethane (2mL), followed by a solution of diiodomethane (1.92mL, 23.8mmol) in dichloromethane (2 mL). After stirring at 0 ℃ for 1h, the mixture is added with 4,4,5, 5-tetramethyl-2- [ (1E) -prop-1-en-1-yl]-a solution of 1,3, 2-dioxaborolan (1000mg, 11.9mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 25 ℃ for 16h and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was extracted with petroleum ether (3 × 50 mL). The combined organic layers were washed with brine (50mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 4,4,5, 5-tetramethyl-2- [ trans-2-methylcyclopropyl ] oil as a yellow oil]1,3, 2-Dioxapentaborane (2000mg, 92%).¹H NMR(400MHz，CDCl₃)δ1.25(s，12H)，1.12–1.11(m，3H)，1.02–0.94(m，1H)，0.75–0.66(m，1H)，0.44–0.35(m，1H)，-0.39–-0.44(m，1H)。

Step 2: trifluoro- [ trans-2-methylcyclopropyl ] potassium borate

To 4,4,5, 5-tetramethyl-2- [ trans-2-methylcyclopropyl group]To a solution of-1, 3, 2-dioxaborolan (1000mg, 5.49mmol) in methanol (10mL) was added a solution of potassium bifluoride (3002mg, 38.45mmol) in water (1 mL). The mixture was stirred at 25 ℃ for 16h and atConcentrating under reduced pressure. The residue was diluted with acetonitrile (5mL) and filtered. The solid was washed with petroleum ether (20mL) to give crude trifluoro- [ trans-2-methylcyclopropyl ] in the form of a white powder]Potassium borate (500mg, 56%).¹H NMR(400MHz，DMSO-d₆)δ0.91(d，J＝6.0Hz，3H)，0.30–0.22(m，1H)，0.00–-0.03(m，1H)，-0.38–-0.40(m，1H)，-1.01–-1.12(m，1H)。

And step 3: (5S,7S) -7-fluoro-5-phenyl-2- [ (1S,2S) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -7-fluoro-5-phenyl-2- [ (1R,2R) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (100mg, 0.35mmol), cesium carbonate (346mg, 1.06mmol), trifluoro- [ trans-2-methylcyclopropyl ] compound]Potassium borate (248mg, 1.53mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl ]]A mixture of palladium (ii) (30mg, 0.04mmol) in 1, 4-dioxane (1mL) and water (0.20mL) was stirred at 110 ℃ under microwave for 3h, then concentrated under reduced pressure. The residue was first passed through preparative TLC (20% ethyl acetate/petroleum ether, R)_f0.4) followed by RP-HPLC (acetonitrile 39-29/0.05% aqueous HCl) to give (5S,7S) -7-fluoro-2- [ trans-2-methylcyclopropyl) as a white solid]-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (15mg, 16%). LCMS R_T3.594 min, 258.3[ M + H ] M/z]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid over 7 minutes) retention time 3.594 minutes, ESI + observed [ M + H ] ═ 258.3.

The material combined from several parallel batches (100mg) was further separated by chiral SFC to give any of the indicated:

(5S,7S) -7-fluoro-2- [ (1S,2S) -2-methylcyclopropyl ] as white solid]-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (peak 1, retention time 3.129 min) (23.8mg, 24%).¹H NMR(400MHz，CD₃OD)δ7.44–7.30(m，3H)，7.22–7.20(m，2H)，6.06–5.87(m，1H)，5.47–5.42(m，1H)，3.73–3.58(m，1H)，2.75–2.60(m，1H)，1.73–1.68(m，1H)，1.32–1.24(m，1H)，1.16(d，J＝6.0Hz，3H)，1.15–1.09(m，1H)，0.82–0.74(m，1H)。LCMS R_T0.858 min, 258.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.858 min, ESI + observed [ M + H ] ═ 258.0.

(5S,7S) -7-fluoro-2- [ (1R,2R) -2-methylcyclopropyl ] as white solid]-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (peak 2, retention time 3.907 min) (28.2mg, 27%).¹H NMR(400MHz，CD₃OD)δ7.47–7.30(m，3H)，7.25–7.17(m，2H)，6.07–5.86(m，1H)，5.46–5.42(m，1H)，3.74–3.60(m，1H)，2.75–2.59(m，1H)，1.73–1.68(m，1H)，1.34–1.29(m，1H)，1.16(d，J＝6.0Hz，3H)，1.12–1.08(m，1H)，0.79–0.74(m，1H)。LCMS R_T0.851 min, 258.0[ M + H ]]⁺。

SFC conditions: column: chiralpak AD-250 × 30mm I.D., 5 um; mobile phase: a: CO2₂B: IPA (0.05% DEA); gradient: 25% to 25% B in 3.5 minutes and hold 40% for 2.5 minutes, then 5% B for 1.5 minutes; flow rate: 50 mL/min; column temperature: at 40 ℃.

Example 97: method 52

(5S,7S) -7-fluoro-2- (1-methylenepropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: trifluoro- (1-methylcyclopropyl) potassium borate

To 4,4,5, 5-tetramethyl-2- (1-methylcyclo)To a solution of propyl) -1,3, 2-dioxaborolan (500mg, 2.75mmol) in methanol (5mL) was added a solution of potassium bifluoride (1501mg, 19.22mmol) in water (0.5 mL). The mixture was stirred at 25 ℃ for 16h and concentrated under reduced pressure. The residue was diluted with acetonitrile (5mL) and filtered. The solid was washed with petroleum ether (20mL) to give crude potassium trifluoro- (1-methylcyclopropyl) borate as a white powder (300mg, 67%).¹H NMR(400MHz，DMSO-d6)δ0.74(s，3H)，0.03–0.03(m，2H)，-0.42–-0.44(m，2H)。

Step 2: (5S,7S) -7-fluoro-2- (1-methylenepropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (150mg, 0.53mmol), cesium carbonate (520mg, 1.60mmol), potassium trifluoro- (1-methylcyclopropyl) borate (290mg, 1.79mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl ]]A mixture of palladium (ii) (44mg, 0.05mmol) in 1, 4-dioxane (1mL) and water (0.20mL) was stirred at 110 ℃ under microwave for 3h and concentrated under reduced pressure. The residue was first passed through preparative TLC (20% ethyl acetate/petroleum ether, R)_f0.4) followed by RP-HPLC (acetonitrile 40-70/0.05% aqueous HCl) to give (5S,7S) -7-fluoro-2- (1-methylenepropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a white solid][1,2,4]Triazole (1.6mg, 1%).¹H NMR(400MHz，CD₃OD)δ7.44–7.33(m，3H)，7.26–7.22(m，2H)，6.15–6.11(m，1H)，6.00–5.98(m，1H)，5.58–5.50(m，1H)，5.32(s，1H)，3.79–3.64(m，1H)，2.80–2.67(m，1H)，2.51(q，J＝7.6Hz，2H)，1.13(t，J＝7.6Hz，3H)。LCMS R_T0.890 min, M/z 257.9[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 2 minutes) retention time 0.890 minutes, ESI + observed [ M + H ] ═ 257.9.

Example 98: method 53

(5S) -2- (cyclopropylmethyl) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: cyclopropyl- [ (5S) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

To cyclopropyl- [ (5S) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 deg.C][1,2,4]Triazol-2-yl]To a solution of methanone (117mg, 0.43mmol) in methanol (2mL) was added sodium borohydride (81mg, 2.16 mmol). The mixture was stirred at 0 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude cyclopropyl- [ (5S) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Methanol (116mg, 98%).¹H NMR(400MHz，CDCl₃)δ7.34–7.27(m，1H)，7.13–7.05(m，2H)，6.93–6.87(m，1H)，5.67–5.61(m，1H)，4.13–4.05(m，1H)，3.29–3.18(m，1H)，3.11–2.93(m，2H)，2.65–2.55(m，1H)，1.41–1.32(m，1H)，0.65–0.36(m，4H)。

Step 2: (5S) -2- (cyclopropylmethyl) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To cyclopropyl- [ (5S) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]To a solution of methanol (96mg, 0.35mmol) in trifluoroacetic acid (2mL, 26.93mmol) was added triethylsilane (2mL, 10.54 mmol). The mixture was stirred at 50 ℃ for 24h and then concentrated under reduced pressure. The residue was added to a saturated aqueous sodium bicarbonate solution (20mL) andextracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 mesh, 200 mesh, 0 to 50% ethyl acetate/petroleum ether) to give (5S) -2- (cyclopropylmethyl) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] as a colorless oil][1,2,4]Triazole (15mg, 16.4%).¹H NMR(400MHz，CD₃OD)δ7.43–7.36(m，1H)，7.22–7.12(m，2H)，7.12–7.06(m，1H)，5.72–5.65(m，1H)，3.30–3.22(m，1H)，3.14–2.97(m，2H)，2.68–2.59(m，1H)，2.59–2.55(m，2H)，1.14–1.03(m，1H)，0.52–0.46(m，2H)，0.23–0.18(m，2H)。LC-MS R_T0.659 min, 258.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.659 min, ESI + observed [ M + H ] ═ 258.1

Example 99: method 54

4- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] isoxazoles

Step 1: trifluoro (isoxazol-4-yl) potassium borate

To a solution of isoxazole-4-boronic acid (300mg, 2.66mmol) in methanol (5mL) was added a solution of potassium bifluoride (1036mg, 13.27mmol) in water (0.30 mL). The mixture was stirred at 25 ℃ for 16h and concentrated under reduced pressure. The residue was diluted with acetonitrile (5 mL). The resulting solid was collected by filtration and washed with petroleum ether (20mL) to give crude potassium trifluoro (isoxazol-4-yl) borate as a yellow solid (400mg, 86%).¹H NMR(400MHz，DMSO-d₆)δ8.20(s，1H)，8.08(s，1H)。

Step 2: 4- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] isoxazoles

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (80mg, 0.28mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl ]]A mixture of palladium (ii) (47mg, 0.06mmol), potassium trifluoro (isoxazol-4-yl) borate (151mg, 0.86mmol) and sodium carbonate (90mg, 0.85mmol) in ethanol (3mL) was stirred at 80 ℃ under microwave conditions for 1h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35-55%/10 mM ammonium bicarbonate/water) to give 4- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Isoxazole (3.4mg, 4%).¹H NMR(400MHz，CD₃OD)δ9.20(s，1H)，8.82(s，1H)，7.44–7.37(m，3H)，7.29–7.28(m，2H)，6.19–6.01(m，1H)，5.61–5.56(m，1H)，3.82–3.68(m，1H)，2.85–2.72(m，1H)LCMS R_T0.828 min, 270.9[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 7 min) retention time 0.828 min, ESI + observed [ M + H ] ═ 270.9.

Example 100: method 55

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] azetidine-3-carbonitrile

Reacting (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole (200mg, 0.71mmol) and [2- (2-aminophenyl) phenyl]Palladium; dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl]A phosphine; a mixture of methanesulfonate (60mg, 0.07mmol), cesium carbonate (693mg, 2.13mmol) and azetidine-3-carbonitrile hydrochloride (168mg, 1.42mmol) was stirred at 90 deg.C under nitrogen for 16 h. The mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with ethyl acetate (3 × 10 mL). Combined organics via sulfurThe sodium salt was dried and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% aqueous ammonia hydroxide solution) to give 1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a red solid][1,2,4]Triazol-2-yl]Azetidine-3-carbonitrile (15.3mg, 8%).¹H NMR(400MHz，CDCl₃)δ7.42–7.35(m，3H)，7.23–7.21(m，2H)，5.98–5.81(m，1H)，5.30–5.29(m，1H)，4.35–4.22(m，4H)，3.63–3.51(m，2H)，2.81–2.70(m，1H)。LCMS R_T1.852 min, M/z 283.9[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 7 minutes) retention time 1.852 minutes, ESI + observed [ M + H ] ═ 283.9.

Example 101: method 56

(5S,7S) -2- [ cyclopropyl (deuterated) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: cyclopropyl-deuterated- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

To a solution of cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanone (300mg, 1.11mmol) in methanol (10mL) was added sodium tetradeuteriborate (93mg, 2.21 mmol). The mixture was stirred for 1h and quenched by the addition of water (20 mL). The solution was extracted with ethyl acetate (3 × 20 mL). The combined organics were washed with brine (2 × 15mL), dried over sodium sulfate and concentrated under reduced pressure to give crude cyclopropyl-deuterated- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol (265mg, 87%) as a white solid.

Step 2: (5S,7S) -2- [ cyclopropyl (deuterated) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To cyclopropyl-deuterated- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]To a solution of methanol (265mg, 0.97mmol) in trifluoroacetic acid (2.0mL, 26.93mmol) was added triethylsilane (2.0mL, 12.50 mmol). The mixture was stirred at 50 ℃ for 12h and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (10mL) and extracted with ethyl acetate (10 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% aqueous ammonia hydroxide solution) to give (5S,7S) -2- [ cyclopropyl (deuterated) methyl group as a white solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (111.4mg, 44%).¹H NMR(400MHz，CDCl₃)¹H NMR(400MHz，CDCl₃)δ7.40–7.35(m，3H)，7.23–7.21(m，2H)，6.05–6.03(m，0.5H)，5.91–5.88(m，0.5H)，5.40–5.37(m，1H)，3.60–3.54(m，1H)，2.89–2.79(m，1H)，2.68–2.63(m，1H)，1.16–1.13(m，1H)，0.56–0.50(m，2H)，0.26–0.23(m，2H)。LCMS R_T1.712 min, 259.2[ M + H ] M/z]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 minutes) retention time 1.712 minutes, ESI + observed [ M + H ] ═ 259.2.

Example 102: method 57

2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] acetonitrile

Step 1: [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

To a solution of cis-7-fluoro-N-methoxy-N-methyl-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carboxamide (3.00g, 103.3mmol) in methanol (70mL) at 0 deg.C was added sodium borohydride (1.95g, 51.7 mmol). The mixture was stirred at 0 ℃ for 2h and quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol as a white solid (2.0g, 83%).

Step 2: 4-Methylbenzenesulfonic acid [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ester

To a solution of [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol (2.0g, 8.57mmol) in tetrahydrofuran (24mL) was added sodium hydride (60% in mineral oil, 515mg, 12.86mmol), followed by p-toluenesulfonic acid (1500mg, 8.57 mmol). The reaction was stirred at 25 ℃ for 12h and quenched by the addition of water (15 mL). The resulting mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate/petroleum ether) to give methyl 4-methylbenzenesulfonate [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] ester (1.8g, 54%) as a colorless oil.

And step 3: 2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] acetonitrile

To 4-methylbenzenesulfonic acid [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazol-2-yl]To a solution of methyl ester (700mg, 1.81mmol) in dimethyl sulfoxide (20mL) was added sodium cyanide (620mg, 12.65 mmol). The mixture was stirred at 90 ℃ for 2h and cooled to 20 ℃. The mixture was diluted with water (50mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. General for residueOver preparative TLC (50% ethyl acetate/petroleum ether, R)_f0.6) to give crude 2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]Acetonitrile (360mg, 82%, 80% purity). A portion of this crude material was further purified by RP-HPLC (30-60% aqueous acetonitrile (0.05% ammonium hydroxide v/v)) to give 2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a colorless oil][1,2,4]Triazol-2-yl]Acetonitrile (26.9mg, 53%).¹H NMR(400MHz，CD₃OD)δ7.43–7.36(m，3H)，7.26–7.23(m，2H)，6.13–6.10(m，0.5H)，5.99–5.96(m，0.5H)，5.56–5.51(m，1H)，3.74–3.67(m，1H)，3.33–3.32(m，2H)，2.81–2.70(m，1H)。LCMS R_T0.870 min, 243.2[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 2.0 minutes) retention time 0.870 minutes, ESI + observed [ M + H ] ═ 243.2.

Example 103: method 58

2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -2-methyl-propionitrile

To 2- [ cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 DEG C][1,2,4]Triazol-2-yl]To a solution of acetonitrile (80mg, 0.33mmol) in N, N-dimethylformamide (2mL) was added sodium hydride (60% in mineral oil, 30mg, 0.74mmol), followed by methyl iodide (0.09mL, 1.49 mmol). The mixture was stirred at 25 ℃ for 1h and quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate/petroleum ether, R)_f0.7) to give 2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a white solid][1,2,4]Triazol-2-yl]-2-methyl-propionitrile (11mg, 11%).¹H NMR(400MHz，CD₃OD)δ7.42–7.36(m，3H)，7.26–7.23(m，2H)，6.13–6.10(m，0.5H)，5.99–5.96(m，0.5H)，5.55–5.51(m，1H)，3.74–3.65(m，1H)，2.81–2.73(m，1H)，1.76(s，6H)。LCMS R_T0.999 min, M/z 271.2[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 2.0 minutes) retention time 0.999 minutes, ESI + observed [ M + H ] ═ 271.2.

Example 104: method 59

(5S,7S) -2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1: cyclopropyl- [ (5S,7S) -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanone

To a solution of (5S,7S) -2-bromo-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (500mg, 1.67mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (430mg, 3.33mmol) in tetrahydrofuran (10mL) at 0 deg.C under a nitrogen atmosphere was added isopropyl magnesium chloride (2.0M in tetrahydrofuran, 4.2mL, 8.4 mmol). The reaction mixture was stirred at 0 ℃ for 2h, then quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude cyclopropyl- [ (5S,7S) -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanone as a green oil (350mg, 72%).

Step 2: (5S,7S) -2- (2-cyclopropyl-1, 3-dithiolan-2-yl) -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a solution of cyclopropyl- [ (5S,7S) -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanone (250mg, 0.86mmol) in dichloromethane (10mL) at 0 deg.C was added 1, 2-ethanedithiol (0.30mL, 3.46mmol) and boron trifluoride diethyl ether (0.12mL, 0.95 mmol). The reaction mixture was stirred at 0 ℃ for 4h, then poured into water (10 mL). The resulting mixture was extracted with dichloromethane (2 × 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 mesh, 200 mesh, 0 to 30% ethyl acetate/petroleum ether) to give 2- (2-cyclopropyl-1, 3-dithiolan-2-yl) -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (250mg, 79%) as a green solid.

And step 3: (5S,7S) -2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a solution of 1-bromo-2, 5-pyrrolidinedione (134mg, 0.75mmol) in dichloromethane (2mL) was added diethylaminosulfur trifluoride (0.2mL, 1.37mmol) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 30 minutes, then (5S,7S) -2- (2-cyclopropyl-1, 3-dithiolan-2-yl) -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] in dichloromethane (0.50mL)][1,2,4]Triazole (250mg, 0.68mmol) was added to the reaction mixture. The resulting mixture was stirred at 0 ℃ for 1h, then quenched by the addition of saturated aqueous sodium bicarbonate solution (2 mL). The resulting mixture was extracted with dichloromethane (2 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 57-87/0.2% formic acid/water) to give (5S,7S) -2- [ cyclopropyl (difluoro) methyl group as a white solid]-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (60.9mg, 28%).¹H NMR(400MHz，CD₃OD)δ7.45–7.42(m，1H)，7.24–7.21(m，2H)，7.11–7.08(m，1H)，6.18–6.02(m，1H)，5.88–5.75(m，1H)，3.83–3.73(m，1H)，2.88–2.80(m，1H)，1.81–1.75(m，1H)，0.75–0.70(m，4H)。LCMS R_T0.809 min, 312.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.809 min, ESI + observed [ M + H ] ═ 312.1.

Example 105: method 60

(R) - (1-methylcyclopropyl) - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

Step 1: N-methoxy-N, 1-dimethylcyclopropanecarboxamide

A mixture of 1-methylcyclopropanecarboxylic acid (1.0g, 9.99mmol), N, N-diisopropylethylamine (3.2g, 24.97mmol), 2- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (5.7g, 14.98mmol) and N, O-dimethylhydroxylamine hydrochloride (2.0g, 19.98mmol) in N, N-dimethylformamide (20mL) was stirred at 25 ℃ for 16h and then quenched by the addition of saturated ammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate/petroleum ether) to give N-methoxy-N, 1-dimethyl-cyclopropanecarboxamide (740mg, 52%) as a colorless oil.¹HNMR(400MHz，CDCl₃)δ3.71(s，3H)，3.22(s，3H)，1.35(s，3H)，1.04–1.01(m，2H)，0.56–0.53(m，2H)。LCMS R_T0.354 min, 144.2[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.354 min, ESI + observed [ M + H ] ═ 144.2.

Step 2: ((5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) (1-methylcyclopropyl) methanone

To N-methoxy-N, 1-dimethyl-cyclopropanecarboxamide (198mg, 1.38mmol) and (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 ℃ under a nitrogen atmosphere][1,2,4]To a solution of triazole (300mg, 1.06mmol) in tetrahydrofuran (2mL) was added isopropyl magnesium chloride (2.0M in tetrahydrofuran, 1.6mL, 3.20 mmol). The mixture was stirred at 0 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a brown solid][1,2,4]Triazol-2-yl]- (1-methylcyclopropyl) methanone (290mg, 96%) which was used as such in the next step. LCMS R_T0.675 min, 286.2[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.675 min, ESI + observed [ M + H ] ═ 286.2.

And step 3: (R) - (1-methylcyclopropyl) - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

To [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 25 DEG C][1,2,4]Triazol-2-yl]To a solution of (1-methylcyclopropyl) methanone (290mg, 1.02mmol) in methanol (10mL) was added sodium borohydride (38mg, 1.02 mmol). The mixture was stirred at 25 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 32-62%/0.05% aqueous ammonia hydroxide solution) to give [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]- (1-methylcyclopropyl) methanol (60mg, 21%). LCMS R_T1.512 min, M/z 288.2[ M + H ]]⁺. LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 min) retention time 1.512 min, ESI + found [ M + H ]]＝288.2。

This material (60mg) was further purified by chiral SFC to give any of the indicated:

(R) - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]- (1-methylcyclopropyl) methanol (peak 2, retention time 4.322 min) (29.7mg, 49%).¹H NMR(400MHz，CDCl₃)δ7.42–7.36(m，3H)，7.21–7.19(m，2H)，6.07–5.90(m，1H)，5.45–5.41(m，1H)，4.30–4.28(m，1H)，3.68–3.53(m，1H)，2.91–2.76(m，2H)，1.07(s，3H)，0.82–0.78(m，1H)，0.64–0.60(m，1H)，0.44–0.37(m，2H)。LCMS R_T0.918 min, 288.2[ M + H ═ M/z]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid for 2 minutes) retention time 0.918 minutes, ESI + observed [ M + H ] ═ 288.2.

SFC conditions: column: chiralpak AD-3150 × 4.6mm i.d., 3um mobile phase: a: CO 2₂B: methanol (0.05% DEA) gradient: 5% to 40% B and hold 40% for 2.5 minutes in 5 minutes, then 5% B for 2.5 minutes, flow rate: 2.5 mL/min, column temperature: 40 deg.C

(S) - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]- (1-methylcyclopropyl) methanol (peak 1, retention time 3.549 min) (27.4mg, 42%).¹H NMR(400MHz，CDCl₃)δ7.42–7.36(m，3H)，7.21–7.19(m，2H)，6.07–5.90(m，1H)，5.45–5.41(m，1H)，4.31(d，J＝4.0Hz，1H)，3.68–3.53(m，1H)，2.91–2.82(m，1H)，2.68(d，J＝8.0Hz，1H)，1.07(s，3H)，0.82–0.78(m，1H)，0.64–0.60(m，1H)，0.44–0.42(m，2H)。LCMS R_T0.918 min, 288.2[ M + H ═ M/z]⁺。

Example 106: method 61

[ (1R,2S) -2-Fluorocyclopropyl ] - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

To [ (1R,2S) -2-fluorocyclopropyl radical at 0 DEG C]- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]To a solution of methanone (110mg, 0.38mmol) in methanol (5mL) was added sodium borohydride (144mg, 3.80 mmol). The mixture was stirred at 25 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60/0.05% aqueous ammonia hydroxide) to give [ (1R,2S) -2-fluorocyclopropyl ] as a white solid]- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]Methanol (35mg, 31%).¹H NMR(400MHz，CDCl₃)δ7.45–7.35(m，3H)，7.24–7.21(m，2H)，6.10–5.86(m，1H)，5.50–5.41(m，1H)，4.81–4.44(m，2H)，3.71–3.51(m，1H)，2.98–2.81(m，1H)，2.73–2.57(m，1H)，1.99–1.62(m，1H)，1.19–1.06(m，1H)，0.91–0.84(m，1H)。LCMS R_T0.766 min, 292.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.766 min, ESI + found [ M + H ] ═ 292.0.

Examples 107 and 109: method 62

(5S,7S) -2- [ (R) -cyclopropyl (fluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -2- [ (S) -cyclopropyl (fluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a cooled (0 ℃) solution of cyclopropyl- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol (180mg, 0.66mmol) in dichloromethane (5mL) was added diethylaminosulfur trifluoride (0.18mL, 1.32 mmol). The mixture was stirred at 0 ℃ for 0.5h and quenched by the addition of ice water (20 mL). The mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25% ethyl acetate/petroleum ether) to give (5S,7S) -2- [ cyclopropyl (fluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (100mg, 55%) as a pale yellow solid. This material was further purified by chiral SFC to give any of the named:

(5S,7S) -2- [ (S) -cyclopropyl (fluoro) methyl group as white solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (peak 1, retention time 2.921 min) (30mg, 30%).¹H NMR(400MHz，CDCl₃)δ7.42–7.37(m，3H)，7.27–7.23(m，2H)，6.08–5.92(m，1H)，5.46–5.42(m，1H)，4.91–4.76(m，1H)，3.69–3.54(m，1H)，2.96–2.84(m，1H)，1.70–1.67(m，1H)，0.79–0.75(m，1H)，0.70–0.62(m，2H)，0.52–0.45(m，1H)。LCMS：R_T1.018 min, M/z 276.2[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% trifluoroacetic acid over 2.0 minutes) retention time 1.018 minutes, ESI + observed [ M + H ] ═ 276.2.

(5S,7S) -2- [ (R) -cyclopropyl (fluoro) methyl group as white solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (peak 2, retention time 3.924 min) (44.8mg, 45%).¹H NMR(400MHz，CDCl₃)δ7.39–7.34(m，3H)，7.23–7.20(m，2H)，6.05–5.88(m，1H)，5.41–5.37(m，1H)，4.86–4.71(m，1H)，3.60–3.52(m，1H)，2.92–2.81(m，1H)，1.65–1.61(m，1H)，0.75–0.70(m，1H)，0.62–0.57(m，2H)，0.45–0.39(m，1H)。R_T0.764 min, 276.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.764 min, ESI + observed [ M + H ] ═ 276.1.

SFC conditions: column: chiralpak AD-3150 × 4.6mm i.d., 3um mobile phase: a: CO 2₂B: ethanol (0.05% DEA) gradient: 5% to 40% of B in 5 minutes and hold 40% for 2.5 minutes, then 5% of B holdFlow rate for 2.5 minutes: 2.5 mL/min, column temperature: 35 ℃ is carried out.

Example 108: method 63

[ (1S,2R) -2-Fluorocyclopropyl ] - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol

To [ (1S,2R) -2-fluorocyclopropyl radical at 25 DEG C]- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]To a solution of methanone (300mg, 1.0mmol) in methanol (10mL) was added sodium borohydride (196mg, 5.2 mmol). The mixture was stirred at 25 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-50/0.05% aqueous ammonia hydroxide) to give [ (1S,2R) -2-fluorocyclopropyl ] as a white solid]- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]Methanol (240mg, 79%).¹H NMR(400MHz，CDCl₃)δ7.43–7.33(m，3H)，7.25–7.20(m，2H)，6.02–5.90(m，1H)，5.46–5.34(m，1H)，4.79–4.44(m，2H)，3.63–3.56(m，1H)，2.93–2.82(m，1H)，1.86–1.83(m，1H)，1.19–1.04(m，1H)，0.92–0.78(m，1H)。LCMS R_T0.769 min, 292.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.769 min, ESI + observed [ M + H ] ═ 292.0.

Examples 110 and 111: method 64

(5S,7S) -7-fluoro-5-phenyl-2- [ (S) -cyclopropyl-deuterated-fluoro-methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole and (5S,7S) -7-fluoro-5-phenyl-2- [ (R) -cyclopropyl-deuterated-fluoro-methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a cooled (0 ℃) solution of cyclopropyl-deuterated- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol (0.15g, 0.55mmol) in dichloromethane (2mL) was added diethylaminosulfur trifluoride (0.29mL, 2.19 mmol). The mixture was stirred at 0 ℃ for 1h and poured into ice water (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 10mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 mesh, 200 mesh, 0 to 16% ethyl acetate/petroleum ether) to give (5S,7S) -2- (cyclopropyl-deuterated-fluoro-methyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole (70mg, 45%) as a white solid. This material was further purified by chiral SFC to give any of the named:

(5S,7S) -7-fluoro-5-phenyl-2- [ (S) -cyclopropyl-deuterated-fluoro-methyl as white solid]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (peak 1, retention time 3.021 min) (14.9mg, 21%).¹H NMR(400MHz，DMSO-d₆)δ7.44–7.36(m，3H)，7.24–7.21(m，2H)，6.25–6.24(m，0.5H)，6.11–6.09(m，0.5H)，5.65–5.62(m，1H)，3.77–3.64(m，1H)，2.75–2.62(m，1H)，1.61–1.58(m，1H)，0.74–0.67(m，1H)，0.60–0.54(m，2H)，0.40–0.37(m，1H)。LCMS R_T0.761 min, 277.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.761 min, ESI + observed [ M + H ] ═ 277.1.

(5S,7S) -7-fluoro-5-phenyl-2- [ (R) -cyclopropyl-deuterated-fluoro-methyl as white solid]-6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (peak 2, retention time 4.052 min) (15.2mg, 21%).¹H NMR(400MHz，CD₃OD)δ7.44–7.37(m，3H)，7.24–7.22(m，2H)，6.14–6.12(m，0.5H)，5.99–5.97(m，0.5H)，5.55–5.51(m，1H)，3.77–3.67(m，1H)，2.80–2.69(m，1H)，1.59–1.52(m，1H)，0.74–0.72(m，1H)，0.61–0.56(m，2H)，0.39–0.33(m，1H)。LCMS R_T0.762 min, 277.2[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 1.5 min) retention time 0.762 min, ESI + observed [ M + H ] ═ 277.2.

SFC conditions: column: AD-3_ etoh (dea) _5_40_2.5M, mobile phase: a: CO 2₂B: ethanol (0.05% DEA) gradient: 5% to 40% B in 5.5 minutes and hold 40% for 3 minutes, then 5% B for 1.5 minutes flow rate: 2.5 mL/min column temperature 40 ℃.

Example 112: method 65

(5S,7S) -2- [ (2, 2-Difluorocyclopropyl) methyl ] -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Step 1:

(5S,7S) -2-allyl-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-bromo-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]A mixture of triazole (1000mg, 3.33mmol), cesium carbonate (3257mg, 10mmol), Ruphos-Pd-G2(259mg, 0.33mmol) and allylboronic acid pinacol ester (1119mg, 6.66mmol) in 1, 4-dioxane (10mL) and water (2.5mL) was stirred at 100 ℃ under nitrogen for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (35% ethyl acetate/petroleum ether, R)_f0.4) to give (5S,7S) -2-allyl-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1, 2-b) as a colorless oil][1,2,4]Triazole (400mg, 46%) was used as such in the next step.

Step 2: (5S,7S) -2- [ (2, 2-Difluorocyclopropyl) methyl ] -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Reacting (5S,7S) -2-allyl-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (300mg, 1.15mmol), tetrabutylammonium bromide (37mg, 0.11mmol) and [ chloro (difluoro) methyl]A mixture of-trimethyl-silane (364mg, 2.30mmol) in toluene (20mL) was stirred under microwave conditions at 110 ℃ for 4 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 48-68/0.2% aqueous formic acid) to give (5S,7S) -2- [ (2, 2-difluorocyclopropyl) methyl as a white solid]-7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b][1,2,4]Triazole (27.9mg, 8%).¹H NMR(400MHz，CD₃OD)δ7.47–7.37(m，1H)，7.23–7.17(m，2H)，7.07–7.02(m，1H)，6.15–5.95(m，1H)，5.83–5.74(m，1H)，3.84–3.66(m，1H)，3.05–2.94(m，1H)，2.88–2.69(m，2H)，2.09–1.94(m，1H)，1.54–1.51(m，1H)，1.25–1.11(m，1H)。LCMS R_T0.769 min, 312.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% ammonium bicarbonate over 1.5 min) retention time 0.769 min, ESI + observed [ M + H ] ═ 312.1.

Example 113: method 66

Rac- (1S,2S) -2- [ difluoro- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ] cyclopropanecarbonitrile

Diethylaminosulfur trifluoride (0.2mL, 1.52mmol) and trans-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ]][1,2,4]Triazole-2-carbonyl]A mixture of cyclopropanecarbonitrile (45mg, 0.15mmol) was stirred at 0 deg.C under nitrogen for 16h and quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with brine (15mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% aqueous HCl) to give rac- (1S,2S) -2- [ difluoro- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a light yellow solid][1,2,4]Triazol-2-yl]Methyl radical]Cyclopropanecarbonitrile (16mg, 30%).¹H NMR(400MHz，CD₃OD)δ7.44–7.38(m，3H)，7.27–7.26(m，2H)，6.18–6.15(m，0.5H)，6.04–6.01(m，0.5H)，5.63–5.60(m，1H)，3.80–3.70(m，1H)，2.86–2.76(m，1H)，2.59–2.57(m，1H)，2.08–2.03(m，1H)，1.49–1.45(m，2H)。LCMS R_T1.785 min, 319.1[ M + H ] M/z]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.785 minutes, ESI + observed [ M + H ] ═ 319.1.

Examples 115 and 116: method 67

(S) -cyclopropyl- [ (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methanol and (R) -cyclopropyl- [ (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methanol

To a mixture of any of the named cyclopropyl- [ (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methanones (100mg, 0.37mmol) in methanol (15mL) was added sodium borohydride (21mg, 0.55 mmol). The mixture was stirred at 25 ℃ for 2h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was separated by chiral SFC to give any of the named:

(S) -cyclopropyl- [ (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] as a white solid]Pyrazol-2-yl]Methanol (peak 1, retention time 3.806 min) (38.0mg, 37%).¹H NMR(400MHz，CDCl₃)δ7.37–7.31(m，3H)，7.19–7.17(m，2H)，6.45(d，J＝2.4Hz，1H)，6.04(d，J＝5.2Hz，0.5H)，5.91–5.89(m，0.5H)，5.41–5.39(m，1H)，4.15–4.12(m，1H)，3.50–3.41(m，1H)，2.81–2.71(m，1H)，2.39(d，J＝3.6Hz，1H)，1.29–1.27(m，1H)，0.63–0.58(m，2H)，0.47–0.39(m，2H)。LCMS R_T0.808 min, M/z 272.9[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.808 min, ESI + observed [ M + H ] ═ 272.9.

(R) -cyclopropyl- [ (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] as a white solid]Pyrazol-2-yl]Methanol (peak 2, retention time 4.181 min) (36.0mg, 35%).¹H NMR(400MHz，CDCl₃)δ7.37–7.31(m，3H)，7.19–7.17(m，2H)，6.45(d，J＝2.4Hz，1H)，6.04(d，J＝5.2Hz，0.5H)，5.91–5.89(m，0.5H)，5.40–5.39(m，1H)，4.15–4.11(m，1H)，3.51–3.41(m，1H)，2.80–2.71(m，1H)，2.43(d，J＝3.6Hz，1H)，1.29–1.27(m，1H)，0.63–0.56(m，2H)，0.48–0.38(m，2H)。LCMS R_T0.816 min, 273.0[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.816 min, ESI + observed [ M + H ] ═ 273.0.

SFC conditions: column: DAICEL CHIRALPAK IC (250mm 30mm, 5um), mobile phase: a: CO 2₂B: ethanol (0.05% DEA) gradient: 5% to 40% B and hold 40% for 3.0 minutes over 5 minutes, then 5% B for 1.5 minutes flow rate: 2.5 mL/min column temperature 40 ℃.

Example 116: method 68

(5S,7S) -2- [ cyclopropyl (dideutero) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

Cyclopropyl-deuterated- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl]A mixture of methanol (100mg, 0.36mmol), triethylsilane-d (0.4mL, 2.48mmol) and trifluoroacetic acid-d (0.4mL, 5.34mmol) was stirred at 50 ℃ for 16h and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (10mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 45-75/0.05% hydrogen oxygen)Aqueous ammonia solution) to give (5S,7S) -2- [ cyclopropyl (dideutero) methyl group as white solid]-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazole (22mg, 21%).¹H NMR(400MHz，CD₃OD)δ7.44–7.33(m，3H)，7.24–7.22(m，2H)，6.15–5.92(m，1H)，5.55–5.44(m，1H)，3.78–3.61(m，1H)，2.80–2.64(m，1H)，1.15–1.03(m，1H)，0.53–0.45(m，2H)，0.26–0.17(m，2H)。LCMS R_T0.995 min, and 260.2[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.1% ammonia over 3.0 minutes) retention time 0.995 minutes, ESI + observed [ M + H ] ═ 260.2.

Example 117: method 69

2, 2-difluoro-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propan-1-ol

Step 1: 2, 2-difluoro-N-methoxy-N-methyl-propionamide

2, 2-Difluoropropionic acid (2.00g, 18.17mmol), N, O-dimethylhydroxylamine hydrochloride (3.54g, 36.34mmol), N-diisopropylethylamine (7.05g, 54.52mmol), and 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]A mixture of pyridinium 3-oxide hexafluorophosphate (7.25g, 19.08mmol) in N, N-dimethylformamide (50mL) was stirred at 20 ℃ for 2 h. The mixture was diluted with water (60mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with water (2 × 20mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 2, 2-difluoro-N-methoxy-N-methyl-propionamide (1.50g, 54%) as a pale yellow oil.¹H NMR(400MHz，CDCl₃)δ3.78–3.69(m，3H)，3.28–3.18(m，2H)，2.81–2.72(m，1H)，1.88–1.74(m，3H)。

Step 2: 2, 2-difluoro-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propane-1, 1-diol

To (5S,7S) -2-bromo-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 ℃ under a nitrogen atmosphere][1,2,4]To a cooled (0 ℃ C.) mixture of triazole (100mg, 0.35mmol), 2-difluoro-N-methoxy-N-methyl-propionamide (54mg, 0.35mmol) in tetrahydrofuran (2mL) was added isopropyl magnesium chloride (2.0M in tetrahydrofuran, 0.18mL, 0.35 mmol). The mixture was stirred at 0 ℃ for 1h and quenched by addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate/petroleum ether, R)_f0.4) to give 2, 2-difluoro-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1, 2-b) as a light brown oil][1,2,4]Triazol-2-yl]Propane-1, 1-diol (30mg, 27%). LCMS R_T0.549 min, 314.1[ M + H ] M/z]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid over 2.0 minutes) retention time 0.549 minutes, ESI + observed [ M + H ] ═ 314.1.

And step 3: 2, 2-difluoro-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propan-1-ol

To 2, 2-difluoro-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] at 0 deg.C][1,2,4]Triazol-2-yl]To a solution of propane-1, 1-diol (30mg, 0.10mmol) in methanol (3mL) was added sodium borohydride (4mg, 0.10 mmol). The mixture was stirred at 0 ℃ for 1h and quenched by the addition of water (3 mL). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (40% -70% aqueous acetonitrile (0.05% ammonium hydroxide v/v)) to give 2, 2-difluoro-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazol-2-yl]Propan-1-ol (12.3mg, 43%).¹H NMR(400MHz，CDCl₃)δ7.40–7.36(m，3H)，7.23–7.15(m，2H)，6.06–5.90(m，1H)，5.49–5.37(m，1H)，5.00–4.84(m，1H)，3.69–3.52(m，1H)，3.30–3.13(m，1H)，3.00–2.81(m，1H)，1.77–1.66(m，3H)。LCMS R_T0.722 min, 298.1[ M + H ]]⁺。

LCMS (5 to 95% acetonitrile/water + 0.03% trifluoroacetic acid for 1.5 min) retention time 0.722 min, ESI + observed [ M + H ] ═ 298.1.

Example 108: method 70

(5R,7R) -2- (difluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole step 1:

cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carbaldehyde

To a mixture of ethyl cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carboxylate (1000mg, 3.63mmol) in dichloromethane (50mL) was added dropwise diisobutylaluminum hydride (1.0M in toluene, 9.08mL, 9.08mmol) at-70 ℃. The reaction mixture was stirred at-70 ℃ for 2h, then quenched by the addition of sodium sulfate decahydrate (10.0 g). The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give crude cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carbaldehyde (1200mg, 100%) as a colorless oil.

Step 2:

(5R,7R) -2- (difluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole

To a solution of cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole-2-carbaldehyde (140mg, 0.61mmol) in dichloromethane (10mL) was added diethylaminosulfur trifluoride (0.4mL, 3.03mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 1h and quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 mesh, 0 to 50% ethyl acetate/petroleum ether) to give cis-2- (difluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole as a colorless oil (90mg, 59%) which was separated by chiral SFC to give the any of the named:

(5R,7R) -2- (difluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (peak 2, retention time 2.621 min) (28mg, 30%).¹H NMR(400MHz，CDCl₃)δ7.43–7.39(m，3H)，7.27–7.24(m，2H)，6.69(t，J＝53.6Hz，1H)，6.11–5.95(m，1H)，5.49–5.45(m，1H)，3.70–3.60(m，1H)，3.01–2.90(m，1H)。LCMS R_T1.649 min, M/z 254.1[ M + H ]]⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.649 minutes, ESI + observed [ M + H ] ═ 254.1.

SFC conditions: column: DAICEL CHIRAL OD (250mmx30mm, 5um) mobile phase: a: CO 2₂B: ethanol (0.1% NH)₃.H₂O) gradient: b flow rate of 15% to 15%: column temperature 50 mL/min: at 40 ℃.

Peak 1 was also collected as: (5S,7S) -2- (difluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] as a white solid][1,2,4]Triazole (peak 1, retention time 2.222 min) (26mg, 29%).¹H NMR(400MHz，CDCl₃)δ7.44–7.40(m，3H)，7.27–7.25(m，2H)，6.83–6.56(m，1H)，6.11–5.95(m，1H)，5.49–5.46(m，1H)，3.70–3.60(m，1H)，3.01–2.91(m，1H)。LCMS R_T1.661 minutes, 254.1(M + H) with M/z⁺。

LCMS (10 to 80% acetonitrile/water + 0.03% ammonium bicarbonate over 3.0 minutes) retention time 1.661 minutes, ESI + observed [ M + H ] ═ 254.1.

RIP1 kinase inhibition assay (biochemical assay):

the ability of the compounds of the invention to inhibit RIP1K activity was tested as described below.

Enzyme assay: the ability of receptor-interacting protein kinase (RIPK1) to catalyze hydrolysis of adenosine-5 '-triphosphate (ATP) was monitored using a Transcreener ADP (adenosine-5' -diphosphate) assay (BellBrook Labs). Purified human RIP1 kinase domain (2-375) (50nM) from a baculovirus-infected insect cell expression system was combined with test compounds in a solution containing 30mM MgCl₂1mM dithiothreitol, 50uM ATP, 0.002% Brij-35, and 0.5% dimethyl sulfoxide (DMSO) in 50mM hepes buffer (pH7.5) for 2 hours. By adding a solution containing an additional 12mM EDTA and 55ug/mL ADP2 antibody and 4nM

633 tracer 1 XBell Brooks Stop buffer B (20mM Hepes (ph7.5), 40mM EDTA and 0.02% Brij-35) quench the reaction. The tracer bound to the antibody was displaced by ADP generated during the RIP1K reaction, which resulted in a decrease in fluorescence polarization measured by laser excitation at 633nm with FP microplate reader M1000. Fractional activity is plotted against test article concentration. Using Genetiata Screener software (Genetidata; Basel, Switzerland), the data were fit to the tight binding apparent inhibition constant (K)_i ^app) Morrison equations [ Williams, J.W. and Morrison, J.F. (1979) The kinetics of reversible light-binding inhibition. methods Enzymol 63: 437-67]. The following equation was used to calculate fractional activity and K_i ^app：

Wherein [ E]_TAnd [ I]_TThe total concentration of active enzyme and test substance, respectively.

Exemplary compounds of the invention are provided in table 1 along with their physicochemical properties and in vitro RIP1 kinase inhibitory activity data. The "method" in the first column of each table refers to the synthetic method used to prepare each compound as shown in the examples above. In certain examples, chiral column retention times (minutes) for certain stereoisomers are provided. Unless otherwise indicated, the stereochemistry shown in each structure indicates the relative configuration of the individual stereoisomers, and the absolute configurations (i.e., "R" and/or "S") are arbitrarily designated. In some embodiments, where the methods are described as involving the separation of stereoisomers, single stereoisomers of the compounds of table 1 are provided.

TABLE 1

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited in this specification are incorporated herein by reference, in their entirety.

Although the foregoing invention has been described in some detail for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R^ASelected from:

s is 0 or 1;

R¹Selected from hydrogen, deuterium, fluoro, methyl and cyano; and is

The ring A and the ring B are fused to form a polycyclic ring system, wherein

Ring a is a 5-membered heteroaromatic ring having (i) two or three nitrogen atoms, (ii) one nitrogen atom and one oxygen atom or (iii) one nitrogen atom and one sulfur atom as its only heteroatoms; wherein said a ring is optionally substituted at a carbon atom with one substituent selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl; and is

The B ring is a 4 to 8 membered carbocyclic ring, or a 4 to 8 membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

p is 1 or 2, and q is 0 or 1; or p is 0 and q is 1;

each R^B1Independently selected from halogen, deuterium, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Thioalkyl, C₁-C₆alkyl-N (R)^N)₂And a cyano group; two of which are C₁-C₆The alkyl substituents may together form a bridged or spiro ring; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, cyano or C having an oxygen or sulfur atom directly bonded to said nitrogen atom₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or C₁-C₆A thioalkyl group;

provided that when R is^AIs composed of

not methyl, tert-butyl, N-ethylmorpholino or methoxyethyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a and ring B together are selected from the following:

wherein

R^3aAnd R^3bOne of which is H and the other is selected from hydrogen, deuterium, fluoro, chloro, hydroxy, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, cyclopropyl, C₁-C₄Alkoxy and C₁-C₄A haloalkoxy group; or

R^3aAnd R^3bEach independently selected from deuterium, fluoro, chloro, hydroxy, cyano and methyl, with the proviso that R is^3aAnd R^3bNot all can be OH or CN; or

R^3aAnd R^3bTogether with the carbon atoms to which they are both attached form a 1, 1-cyclopropylene group; and is

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring a and ring B together are:

wherein

R^3aAnd R^3bThe following options are selected:

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring a and ring B together are selected from the following:

wherein

R^3aAnd R^3bTogether with the carbon atoms to which they are both attached form a 1, 1-cyclopropylene group; and each R⁵Independently selected from H, F, Cl, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy and C₁-C₆A haloalkoxy group; and is

m is 0, 1,2 or 3.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A and ring B together are:

wherein

Each R⁵Selected from hydrogen, fluorine, chlorine, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy and C₁-C₆A haloalkoxy group; and is

m is 0, 1,2 or 3.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a and ring B together are:

wherein

m is 0, 1,2 or 3.

7. A compound of claim 4,5 or 6, or a pharmaceutically acceptable salt thereof, wherein R⁵Selected from H, F, Cl, CH₃、CH₂CH₃、OCH₃、CF₃、OCF₃、CF₂H and OCF₂H。

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein

R¹Selected from hydrogen, fluorine, hydroxy, cyano, CH₂CN、C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy and 4 to 5 membered heterocyclyl;

m is 0, 1,2 or 3;

R^2aand R^2bEach independently selected from hydrogen, deuterium, fluorine, hydroxyl, C₁-C₃Alkyl radical, C₁-C₃A fluoroalkyl group; or

R¹Is hydrogen, deuterium, fluoro, methyl or cyano, and R^2aAnd R^2bTogether with the carbon atoms to which they are both attached form a 1, 1-cyclopropylene group optionally substituted with one or two substituents selected from: F. c_1-3Alkyl, hydroxy, hydroxymethyl, methoxymethyl, cyano, CO₂-C_1-3Alkyl, trifluoromethyl, difluoromethoxy and trifluoroAnd (3) methoxy.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R^AIs composed of

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof,

wherein

Selected from the following:

11. the compound of claim 9 or a pharmaceutically acceptable salt thereof,

wherein

Selected from the following:

12. a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the following:

cis-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propan-1-ol;

cis-2- (1, 1-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-7-fluoro-2- (1-fluoropropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-2, 2, 2-trifluoro-1- (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) ethanol;

cis-2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-7-fluoro-2- (1-fluoro-1-methyl-propyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R) -1-fluoropropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-2- ((S) -1-fluoropropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-2- (1, 1-difluoro-2, 2-dimethyl-propyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-2-cyclopropyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

cis-7-fluoro-5-phenyl-2- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5R,7R) -7-fluoro-5-phenyl-2- (3,3, 3-trifluoropropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

trans-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] cyclopropanecarbonitrile;

rac- (5S,7S) -2- [ difluoro- (3-methyloxetan-3-yl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2- (3,3, 3-trifluoropropyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-2- (1-methylpyrazol-3-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- [ (2, 2-difluorocyclopropyl) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac-ethyl- (1R,2R) -2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] cyclopropanecarboxylate;

3- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propionitrile;

rac- (5S,7S) -2- [ difluoro- [ rac- (1R,2R) -2-fluorocyclopropyl ] methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R,2R) -2- (methoxymethyl) cyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-2- (4-methylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S) -5- (2-fluorophenyl) -2-propyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-2- ((S) -2-fluorobut-2-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- (2, 2-difluorocyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- (3, 3-difluoropropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- (2, 2-dimethylcyclopropyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2-pyrazol-1-yl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-2- ((R) -2-fluorobut-2-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2- [2- (trifluoromethyl) cyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (S) -cyclopropyl- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol;

rac- (R) -cyclopropyl- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol;

(5S,7S) -7-fluoro-2- (isopropoxymethyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- (2-ethoxyethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (4-isopropylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-4-carbaldehyde;

(5S,7S) -7-fluoro-5-phenyl-2- (4-pyrimidin-4-ylpyrazol-1-yl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- [ 1-bicyclo [1.1.1] pentyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -2- (2-cyclopropylethynyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

rac- (5S,7S) -7-fluoro-5-phenyl-2-prop-1-ynyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- ((R) -bicyclo [1.1.1] pent-1-ylfluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- ((S) -bicyclo [1.1.1] pent-1-ylfluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

1- [ [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ] cyclopropanecarbonitrile;

2-fluoro-2- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] acetonitrile;

(5S,7S) -7-fluoro-2- [ (E) -2- (1-methylpyrazol-4-yl) vinyl ] -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2-vinyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

2- [ (7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl) methoxy ] acetonitrile;

(5S,7S) -2-allyl-7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-3-carbonitrile;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazole-4-carbonitrile;

3- [ [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methylene ] cyclobutanenitrile;

(5S,7S) -7-fluoro-5-phenyl-2- [4- (trifluoromethyl) pyrazol-1-yl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (4-methoxypyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (4-fluoropyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- (4-ethylpyrazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- (4-chloropyrazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (1-methylimidazol-2-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [4- (trifluoromethyl) imidazol-1-yl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (5-methylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [3- (trifluoromethyl) pyrazol-1-yl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

5-amino-1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -3-methyl-pyrazole-4-carbonitrile;

(5S,7S) -7-fluoro-2-imidazol-1-yl-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (2-methylimidazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- (1,2, 4-triazol-1-yl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- (2-chloroimidazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- (4, 5-dimethylimidazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -3-methyl-imidazol-2-one;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] indazole-4-carbonitrile;

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] indazole;

(5S,7S) -7-fluoro-2- (5-methyl-1, 2, 4-triazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- (4-chloroimidazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (4-fluoroimidazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

2- [1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazol-4-yl ] acetonitrile;

1- [1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazol-4-yl ] ethanone;

(5S,7S) -2- (4-cyclopropylpyrazol-1-yl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (4-methanesulfonylpyrazol-1-yl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole;

5-chloro-1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole;

3- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] triazolo [4,5-c ] pyridine;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazolo [4,3-b ] pyridine;

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole-5-carbonitrile;

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -4,5,6, 7-tetrahydrobenzotriazole;

1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazolo [3,4-c ] pyridine;

5-methyl-1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] benzotriazole;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] pyrazolo [4,3-c ] pyridine;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] triazolo [4,5-c ] pyridine;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -5-methyl-pyrazole-3-carbonitrile;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -3-methyl-pyrazole-4-carbonitrile;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] -5-methyl-pyrazole-4-carbonitrile;

(5S,7S) -2- (cyclobutylmethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1S,2S) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (1R,2R) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-2- (1-methylenepropyl) -5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S) -2- (cyclopropylmethyl) -5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

4- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] isoxazole;

1- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] azetidine-3-carbonitrile;

(5S,7S) -2- [ cyclopropyl (deuterated) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] acetonitrile;

2-methyl-2- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propionitrile;

(5S,7S) -2- [ cyclopropyl (difluoro) methyl ] -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(R) - (1-methylcyclopropyl) - [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol;

[ (1R,2S) -2-fluorocyclopropyl ] - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol;

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (R) -cyclopropyl (fluoro) methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

[ (1S,2R) -2-fluorocyclopropyl ] - [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methanol;

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (S) -cyclopropyl (fluoro) methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (R) -cyclopropyl-deuterated-fluoro-methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ rac- (S) -cyclopropyl-deuterated-fluoro-methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- [ (2, 2-difluorocyclopropyl) methyl ] -7-fluoro-5- (2-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(1S,2S) -2- [ difluoro- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ] cyclopropanecarbonitrile;

(R) -cyclopropyl- [ rac- (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methanol;

(S) -cyclopropyl- [ rac- (4R,6R) -4-fluoro-6-phenyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methanol;

(5S,7S) -2- [ cyclopropyl (dideutero) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

2, 2-difluoro-1- [ rac- (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] propan-1-ol; and the combination of (a) and (b),

(5R,7R) -2- (difluoromethyl) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from the following:

rac- (1S,2S) -2- [ difluoro- [ (5S,7S) -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-2-yl ] methyl ] cyclopropanecarbonitrile;

(5S,7S) -2- [ (S) -cyclopropyl (fluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- [ (R) -cyclopropyl (fluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ (S) -cyclopropyl-deuterated-fluoro-methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ (R) -cyclopropyl-deuterated-fluoro-methyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -2- [ 1-bicyclo [1.1.1] pentyl (difluoro) methyl ] -7-fluoro-5-phenyl-6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole;

(5S,7S) -7-fluoro-5-phenyl-2- [ (1S,2S) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole; and

(5S,7S) -7-fluoro-5-phenyl-2- [ (1R,2R) -2-methylcyclopropyl ] -6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazole.

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, having RIP1 kinase inhibitory activity K of less than 100nM_i。

15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for use as therapeutically active substance.

17. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for use in the treatment of a disease or condition selected from: parkinson's disease, dementia with lewy bodies, multiple system atrophy, parkinsonism plus syndrome, tauopathies, alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, adrenocortical degeneration and demyelinating diseases.

18. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for the treatment of a disease or disorder selected from parkinson's disease, dementia with lewy bodies, multiple system atrophy, parkinson's plus syndrome, tauopathy, alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, adrenocortical degeneration and demyelinating diseases.

19. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment of a disease or disorder selected from parkinson's disease, dementia with lewy bodies, multiple system atrophy, parkinsonism plus syndrome, tauopathies, alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, adrenocortical degeneration and demyelinating diseases.

20. A method for treating a disease or disorder in a human, the method comprising administering to the human a therapeutically effective amount of a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15, wherein the disease or disorder is selected from parkinson's disease, lewy body dementia, multiple system atrophy, parkinson's plus syndrome, tauopathy, alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, genetic muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, adrenocortical degeneration, and demyelinating disease.

21. The method of claim 20, wherein the disease or disorder is alzheimer's disease.

22. The method of claim 20, wherein the disease or disorder is multiple sclerosis.

23. The method of claim 20, wherein the disease or disorder is parkinson's disease.

24. The method of claim 20, wherein the disease or disorder is amyotrophic lateral sclerosis.

25. The method of claim 20, wherein the disease or disorder is huntington's disease.

26. The method of claim 20, wherein the disease or disorder is spinal muscular atrophy.

27. A compound of formula II:

or a pharmacologically acceptable salt thereof.

28. The invention as hereinbefore described.